Characterizing the Structure, Function, and Evolution of Human Solute Carrier (SLC) Transporters Using Computational Approaches

  • Avner Schlessinger
Part of the Springer Series in Biophysics book series (BIOPHYSICS, volume 17)


Solute Carrier (SLC) transporters are membrane proteins that transport a broad range of solutes including metabolites, ions, toxins, and prescription drugs. In humans, there are about 400 SLC members, many of which are of medical importance. They can be drug target themselves (e.g., the serotonin transporter, SERT) or regulate the absorption, distribution, metabolism, and excretion (ADME) of drugs (e.g., the organic cation transporter 1, OCT-1). An important step toward describing the mechanisms of solute transport by SLC transporters includes computational or experimental characterization of their ligand-bound or unbound structures in different conformations. Due to a variety of technical issues, human SLC transporters are challenging targets for both experimental and computational characterizations. However, recent advances in computational approaches such as molecular docking and comparative modeling, coupled with the atomic structure determination of several membrane transporters, expanded our ability to characterize the human SLC families using in silico structure-based approaches. In this chapter, we first provide an overview of the structure, function, and pharmacology of the human SLC transporters. Second, we describe different computational methods, including sequence analysis, structural modeling, and ligand docking, that are commonly used, in combination with experimental testing, to characterize the human SLC transporters. Third, we demonstrate the utility of these approaches to characterize SLC members with three examples—the norepinephrine transporter (NET), the γ-aminobutyric acid (GABA) transporter 2 (GAT-2), and the l-type amino acid transporter (LAT-1). Finally, future directions in the field of computational structural biology of human SLC transporters are discussed.


Comparative modeling Membrane protein Molecular docking Protein function prediction Structure-based ligand discovery Virtual screening 



I am grateful to Greg Madej (UCLA) and Hao Fan (UCSF) for helpful comments on the manuscript. I am also thankful to Andrej Sali, Kathleen Giacomini, Ethan Geier, Sook Wah Yee, Matthias Wittwer, Robert Stroud, Andrew Waight, Bjørn Pedersen, Arik Zur, Ligong Chen, Ursula Pieper, Ben Webb, Massimiliano Bonomi, John Irwin, and Brian Shoichet (all UCSF), as well as to Christof Grewer (SUNY Binghamton), David Smith (University of Michigan Ann Arbor), Nir Ben-Tal (TAU), Lucy Forrest (NIH), Ron Kaback (UCLA), Christine Ziegler (MPIBP Frankfurt), Reinhard Krämer (University of Cologne), and Seok-Yong Lee (Duke) for discussions about SLC transporters, structural modeling, ligand docking, and related research.


  1. Abramson J, Wright EM (2009) Structure and function of Na(+)-symporters with inverted repeats. Curr Opin Struct Biol 19(4):425–432. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  2. Adamus WS, Leonard JP, Troger W (1995) Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci 56(11–12):883–890PubMedGoogle Scholar
  3. Adekola K, Rosen ST, Shanmugam M (2012) Glucose transporters in cancer metabolism. Curr Opin Oncol 24(6):650–654. doi: 10.1097/CCO.0b013e328356da72 PubMedGoogle Scholar
  4. Albers T, Marsiglia W, Thomas T, Gameiro A, Grewer C (2012) Defining substrate and blocker activity of alanine–serine–cysteine transporter 2 (ASCT2) ligands with novel serine analogs. Mol Pharmacol 81(3):356–365. doi: 10.1124/mol.111.075648 PubMedCentralPubMedGoogle Scholar
  5. Alexander GM, Schwartzman RJ, Grothusen JR, Gordon SW (1994) Effect of plasma levels of large neutral amino acids and degree of parkinsonism on the blood-to-brain transport of levodopa in naive and MPTP parkinsonian monkeys. Neurology 44(8):1491–1499PubMedGoogle Scholar
  6. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410. doi: 10.1006/jmbi.1990.9999, S0022283680799990 [pii]PubMedGoogle Scholar
  7. Baker D, Sali A (2001) Protein structure prediction and structural genomics. Science 294(5540):93–96PubMedGoogle Scholar
  8. Berardi MJ, Shih WM, Harrison SC, Chou JJ (2011) Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching. Nature 476(7358):109–113. doi: 10.1038/nature10257 PubMedCentralPubMedGoogle Scholar
  9. Bernsel A, Viklund H, Falk J, Lindahl E, von Heijne G, Elofsson A (2008) Prediction of membrane-protein topology from first principles. Proc Natl Acad Sci U S A 105(20):7177–7181. doi: 10.1073/pnas.0711151105, 0711151105 [pii]PubMedCentralPubMedGoogle Scholar
  10. Bernsel A, Viklund H, Hennerdal A, Elofsson A (2009) TOPCONS: consensus prediction of membrane protein topology. Nucleic Acids Res 37(Web Server issue):W465–W468. doi: 10.1093/nar/gkp363 PubMedCentralPubMedGoogle Scholar
  11. Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11(7):780–789. doi: 10.1038/nn.2146, nn.2146 [pii]PubMedCentralPubMedGoogle Scholar
  12. Beuming T, Shi L, Javitch JA, Weinstein H (2006) A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. Mol Pharmacol 70(5):1630–1642. doi: 10.1124/mol.106.026120, mol.106.026120 [pii]PubMedGoogle Scholar
  13. Borhani DW, Shaw DE (2012) The future of molecular dynamics simulations in drug discovery. J Comput Aided Mol Des 26(1):15–26. doi: 10.1007/s10822-011-9517-y PubMedCentralPubMedGoogle Scholar
  14. Bowie JU, Luthy R, Eisenberg D (1991) A method to identify protein sequences that fold into a known three-dimensional structure. Science 253(5016):164–170PubMedGoogle Scholar
  15. Brooijmans N, Kuntz ID (2003) Molecular recognition and docking algorithms. Annu Rev Biophys Biomol Struct 32:335–373. doi: 10.1146/annurev.biophys.32.110601.142532 PubMedGoogle Scholar
  16. Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK (2011) Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol 7(11):769–778. doi: 10.1038/nchembio.662 PubMedCentralPubMedGoogle Scholar
  17. Cavasotto CN, Orry AJ, Murgolo NJ, Czarniecki MF, Kocsi SA, Hawes BE, O’Neill KA, Hine H, Burton MS, Voigt JH, Abagyan RA, Bayne ML, Monsma FJ Jr (2008) Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening. J Med Chem 51(3):581–588. doi: 10.1021/jm070759m PubMedGoogle Scholar
  18. Celik L, Sinning S, Severinsen K, Hansen CG, Moller MS, Bols M, Wiborg O, Schiott B (2008) Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation. J Am Chem Soc 130(12):3853–3865. doi: 10.1021/ja076403h PubMedGoogle Scholar
  19. Chang JM, Di Tommaso P, Taly JF, Notredame C (2012) Accurate multiple sequence alignment of transmembrane proteins with PSI-Coffee. BMC Bioinformatics 13(Suppl 4):S1. doi: 10.1186/1471-2105-13-S4-S1 PubMedCentralPubMedGoogle Scholar
  20. Chen NH, Reith ME, Quick MW (2004) Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch 447(5):519–531. doi: 10.1007/s00424-003-1064-5 PubMedGoogle Scholar
  21. Choi JH, Yee SW, Ramirez AH, Morrissey KM, Jang GH, Joski PJ, Mefford JA, Hesselson SE, Schlessinger A, Jenkins G, Castro RA, Johns SJ, Stryke D, Sali A, Ferrin TE, Witte JS, Kwok PY, Roden DM, Wilke RA, McCarty CA, Davis RL, Giacomini KM (2011) A common 5’-UTR variant in MATE2-K is associated with poor response to metformin. Clin Pharmacol Ther 90(5):674–684. doi: 10.1038/clpt.2011.165 PubMedCentralPubMedGoogle Scholar
  22. Claxton DP, Quick M, Shi L, de Carvalho FD, Weinstein H, Javitch JA, McHaourab HS (2010) Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters. Nat Struct Mol Biol 17(7):822–829. doi: 10.1038/nsmb.1854 PubMedCentralPubMedGoogle Scholar
  23. Coupez B, Lewis RA (2006) Docking and scoring—theoretically easy, practically impossible? Curr Med Chem 13(25):2995–3003PubMedGoogle Scholar
  24. Crisman TJ, Qu S, Kanner BI, Forrest LR (2009) Inward-facing conformation of glutamate transporters as revealed by their inverted-topology structural repeats. Proc Natl Acad Sci U S A 106(49):20752–20757. doi: 10.1073/pnas.0908570106 PubMedCentralPubMedGoogle Scholar
  25. DeBerardinis RJ, Thompson CB (2012) Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148(6):1132–1144. doi: 10.1016/j.cell.2012.02.032 PubMedCentralPubMedGoogle Scholar
  26. Dresser MJ, Gray AT, Giacomini KM (2000) Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1). J Pharmacol Exp Ther 292(3):1146–1152PubMedGoogle Scholar
  27. Elofsson A, von Heijne G (2007) Membrane protein structure: prediction versus reality. Annu Rev Biochem 76:125–140. doi: 10.1146/annurev.biochem.76.052705.163539 PubMedGoogle Scholar
  28. Enkavi G, Li J, Mahinthichaichan P, Wen PC, Huang Z, Shaikh SA, Tajkhorshid E (2013) Simulation studies of the mechanism of membrane transporters. Methods Mol Biol 924:361–405. doi: 10.1007/978-1-62703-017-5_14 PubMedGoogle Scholar
  29. Eramian D, Eswar N, Shen MY, Sali A (2008) How well can the accuracy of comparative protein structure models be predicted? Protein Sci 17(11):1881–1893. doi: 10.1110/ps.036061.108, ps.036061.108 [pii]PubMedCentralPubMedGoogle Scholar
  30. Evers A, Gohlke H, Klebe G (2003) Ligand-supported homology modelling of protein binding-sites using knowledge-based potentials. J Mol Biol 334(2):327–345PubMedGoogle Scholar
  31. Eyre TA, Partridge L, Thornton JM (2004) Computational analysis of alpha-helical membrane protein structure: implications for the prediction of 3D structural models. Protein Eng Des Sel 17(8):613–624. doi: 10.1093/protein/gzh072 PubMedGoogle Scholar
  32. Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, Hirayama BA, Wright EM, Abramson J (2008) The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321(5890):810–814PubMedCentralPubMedGoogle Scholar
  33. Fan H, Irwin JJ, Sali A (2012) Virtual ligand screening against comparative protein structure models. Methods Mol Biol 819:105–126. doi: 10.1007/978-1-61779-465-0_8 PubMedCentralPubMedGoogle Scholar
  34. Fan H, Irwin JJ, Webb BM, Klebe G, Shoichet BK, Sali A (2009) Molecular docking screens using comparative models of proteins. J Chem Inf Model 49(11):2512–2527. doi: 10.1021/ci9003706 PubMedCentralPubMedGoogle Scholar
  35. Fan H, Schneidman-Duhovny D, Irwin JJ, Dong G, Shoichet BK, Sali A (2011) Statistical potential for modeling and ranking of protein–ligand interactions. J Chem Inf Model 51(12):3078–3092. doi: 10.1021/ci200377u PubMedCentralPubMedGoogle Scholar
  36. Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, Williams C, Xiong Y, Miller C (2009) Structure of a prokaryotic virtual proton pump at 3.2 A resolution. Nature 460(7258):1040–1043. doi: 10.1038/nature08201, nature08201 [pii]PubMedCentralPubMedGoogle Scholar
  37. Faraldo-Gomez JD, Forrest LR (2011) Modeling and simulation of ion-coupled and ATP-driven membrane proteins. Curr Opin Struct Biol 21(2):173–179. doi: 10.1016/ PubMedGoogle Scholar
  38. Feng B, Dresser MJ, Shu Y, Johns SJ, Giacomini KM (2001) Arginine 454 and lysine 370 are essential for the anion specificity of the organic anion transporter, rOAT3. Biochemistry 40(18):5511–5520, bi002841o [pii]PubMedGoogle Scholar
  39. Fernandez-Fuentes N, Zhai J, Fiser A (2006) ArchPRED: a template based loop structure prediction server. Nucleic Acids Res 34(Web Server issue):W173–W176. doi: 10.1093/nar/gkl113 PubMedCentralPubMedGoogle Scholar
  40. Fiser A, Sali A (2003) ModLoop: automated modeling of loops in protein structures. Bioinformatics 19(18):2500–2501PubMedGoogle Scholar
  41. Forrest LR (2013) Structural biology. (Pseudo-)symmetrical transport. Science 339(6118):399–401. doi: 10.1126/science.1228465 PubMedGoogle Scholar
  42. Forrest LR, Kramer R, Ziegler C (2011) The structural basis of secondary active transport mechanisms. Biochim Biophys Acta 1807(2):167–188. doi: 10.1016/j.bbabio.2010.10.014 PubMedGoogle Scholar
  43. Forrest LR, Rudnick G (2009) The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda) 24:377–386. doi: 10.1152/physiol.00030.2009, 24/6/377 [pii]Google Scholar
  44. Forrest LR, Tang CL, Honig B (2006) On the accuracy of homology modeling and sequence alignment methods applied to membrane proteins. Biophys J 91(2):508–517PubMedCentralPubMedGoogle Scholar
  45. Forrest LR, Zhang YW, Jacobs MT, Gesmonde J, Xie L, Honig BH, Rudnick G (2008) Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci U S A 105(30):10338–10343PubMedCentralPubMedGoogle Scholar
  46. Gao X, Lu F, Zhou L, Dang S, Sun L, Li X, Wang J, Shi Y (2009) Structure and mechanism of an amino acid antiporter. Science 324(5934):1565–1568. doi: 10.1126/science.1173654, 1173654 [pii]PubMedGoogle Scholar
  47. Gao X, Zhou L, Jiao X, Lu F, Yan C, Zeng X, Wang J, Shi Y (2010) Mechanism of substrate recognition and transport by an amino acid antiporter. Nature 463(7282):828–832. doi: 10.1038/nature08741 PubMedGoogle Scholar
  48. Geier EG, Schlessinger A, Fan H, Gable JE, Irwin JJ, Sali A, Giacomini KM (2013) Structure-based ligand discovery for the large-neutral amino acid transporter 1, LAT-1. Proc Natl Acad Sci U S A 110(14):5480–5485. doi: 10.1073/pnas.1218165110 PubMedCentralPubMedGoogle Scholar
  49. Gether U, Andersen PH, Larsson OM, Schousboe A (2006) Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci 27(7):375–383PubMedGoogle Scholar
  50. Ghersi D, Sanchez R (2012) Automated identification of binding sites for phosphorylated ligands in protein structures. Proteins 80(10):2347–2358. doi: 10.1002/prot.24117 PubMedGoogle Scholar
  51. Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9(3):215–236. doi: 10.1038/nrd3028 PubMedGoogle Scholar
  52. Gruswitz F, Chaudhary S, Ho JD, Schlessinger A, Pezeshki B, Ho CM, Sali A, Westhoff CM, Stroud RM (2010) Function of human Rh based on structure of RhCG at 2.1 A. Proc Natl Acad Sci U S A 107(21):9638–9643. doi: 10.1073/pnas.1003587107 PubMedCentralPubMedGoogle Scholar
  53. Guan L, Kaback HR (2006) Lessons from lactose permease. Annu Rev Biophys Biomol Struct 35:67–91. doi: 10.1146/annurev.biophys.35.040405.102005 PubMedCentralPubMedGoogle Scholar
  54. Guastella J, Nelson N, Nelson H, Czyzyk L, Keynan S, Miedel MC, Davidson N, Lester HA, Kanner BI (1990) Cloning and expression of a rat brain GABA transporter. Science 249(4974):1303–1306PubMedGoogle Scholar
  55. Hahn MK, Blakely RD (2007) The functional impact of SLC6 transporter genetic variation. Annu Rev Pharmacol Toxicol 47:401–441. doi: 10.1146/annurev.pharmtox.47.120505.105242 PubMedGoogle Scholar
  56. Harrington SE, Ben-Tal N (2009) Structural determinants of transmembrane helical proteins. Structure 17(8):1092–1103. doi: 10.1016/j.str.2009.06.009 PubMedGoogle Scholar
  57. Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004) The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction. Pflugers Arch 447(5):465–468PubMedGoogle Scholar
  58. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447. doi: 10.1021/ct700301q Google Scholar
  59. Hill JR, Deane CM (2013) MP-T: improving membrane protein alignment for structure prediction. Bioinformatics 29(1):54–61. doi: 10.1093/bioinformatics/bts640 PubMedGoogle Scholar
  60. Hopf TA, Colwell LJ, Sheridan R, Rost B, Sander C, Marks DS (2012) Three-dimensional structures of membrane proteins from genomic sequencing. Cell 149(7):1607–1621. doi: 10.1016/j.cell.2012.04.012 PubMedCentralPubMedGoogle Scholar
  61. Huang N, Shoichet BK, Irwin JJ (2006) Benchmarking sets for molecular docking. J Med Chem 49(23):6789–6801. doi: 10.1021/jm0608356 PubMedCentralPubMedGoogle Scholar
  62. Irwin JJ, Shoichet BK (2005) ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 45(1):177–182PubMedCentralPubMedGoogle Scholar
  63. Jacobson M, Sali A (2004) Comparative protein structure modeling and its applications to drug discovery. In: Overington J (ed) Annual reports in medicinal chemistry, vol 39. Inpharmatica Ltd, London, pp 259–276Google Scholar
  64. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B, Shaw DE, Friesner RA (2004) A hierarchical approach to all-atom protein loop prediction. Proteins 55(2):351–367. doi: 10.1002/prot.10613 PubMedGoogle Scholar
  65. Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211(5052):969–970PubMedGoogle Scholar
  66. Johnson ZL, Cheong CG, Lee SY (2012) Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 A. Nature 483(7390):489–493. doi: 10.1038/nature10882 PubMedCentralPubMedGoogle Scholar
  67. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T, Kanai Y, Endou H, Nakajima T, Mori M (2008) Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I–III nonsmall cell lung cancer. Br J Cancer 98(4):742–748. doi: 10.1038/sj.bjc.6604235 PubMedCentralPubMedGoogle Scholar
  68. Kall L, Krogh A, Sonnhammer EL (2005) An HMM posterior decoder for sequence feature prediction that includes homology information. Bioinformatics 21(Suppl 1):i251–i257. doi: 10.1093/bioinformatics/bti1014 PubMedGoogle Scholar
  69. Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4 F2 antigen (CD98). J Biol Chem 273(37):23629–23632PubMedGoogle Scholar
  70. Kanner BI, Zomot E (2008) Sodium-coupled neurotransmitter transporters. Chem Rev 108(5):1654–1668. doi: 10.1021/cr078246a PubMedGoogle Scholar
  71. Katoh K, Toh H (2008) Recent developments in the MAFFT multiple sequence alignment program. Brief Bioinform 9(4):286–298. doi: 10.1093/bib/bbn013 PubMedGoogle Scholar
  72. Kaufmann KW, Dawson ES, Henry LK, Field JR, Blakely RD, Meiler J (2009) Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies. Proteins 74(3):630–642. doi: 10.1002/prot.22178 PubMedCentralPubMedGoogle Scholar
  73. Kaufmann KW, Meiler J (2012) Using RosettaLigand for small molecule docking into comparative models. PLoS One 7(12):e50769. doi: 10.1371/journal.pone.0050769 PubMedCentralPubMedGoogle Scholar
  74. Kelm S, Shi J, Deane CM (2009) iMembrane: homology-based membrane-insertion of proteins. Bioinformatics 25(8):1086–1088. doi: 10.1093/bioinformatics/btp102 PubMedCentralPubMedGoogle Scholar
  75. Kelm S, Shi J, Deane CM (2010) MEDELLER: homology-based coordinate generation for membrane proteins. Bioinformatics 26(22):2833–2840. doi: 10.1093/bioinformatics/btq554 PubMedCentralPubMedGoogle Scholar
  76. Kernytsky A, Rost B (2003) Static benchmarking of membrane helix predictions. Nucleic Acids Res 31(13):3642–3644PubMedCentralPubMedGoogle Scholar
  77. Khafizov K, Staritzbichler R, Stamm M, Forrest LR (2010) A study of the evolution of inverted-topology repeats from LeuT-fold transporters using AlignMe. Biochemistry 49(50):10702–10713. doi: 10.1021/bi101256x PubMedGoogle Scholar
  78. Khalili-Araghi F, Gumbart J, Wen PC, Sotomayor M, Tajkhorshid E, Schulten K (2009) Molecular dynamics simulations of membrane channels and transporters. Curr Opin Struct Biol 19(2):128–137. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  79. Kiefer F, Arnold K, Kunzli M, Bordoli L, Schwede T (2009) The SWISS-MODEL repository and associated resources. Nucleic Acids Res 37(Database issue):D387–D392. doi: 10.1093/nar/gkn750 PubMedCentralPubMedGoogle Scholar
  80. Kobayashi K, Ohnishi A, Promsuk J, Shimizu S, Kanai Y, Shiokawa Y, Nagane M (2008) Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells. Neurosurgery 62(2):493–503. doi: 10.1227/01.neu.0000316018.51292.19, discussion 503–494PubMedGoogle Scholar
  81. Kowalczyk L, Ratera M, Paladino A, Bartoccioni P, Errasti-Murugarren E, Valencia E, Portella G, Bial S, Zorzano A, Fita I, Orozco M, Carpena X, Vazquez-Ibar JL, Palacin M (2011a) Molecular basis of substrate-induced permeation by an amino acid antiporter. Proc Natl Acad Sci U S A 108(10):3935–3940. doi: 10.1073/pnas.1018081108 PubMedCentralPubMedGoogle Scholar
  82. Kowalczyk L, Ratera M, Paladino A, Bartoccioni P, Errasti-Murugarren E, Valencia E, Portella G, Bial S, Zorzano A, Fita I, Orozco M, Carpena X, Vazquez-Ibar JL, Palacin M (2011b) Molecular basis of substrate-induced permeation by an amino acid antiporter. Proc Natl Acad Sci U S A 108(10):3935–3940. doi: 10.1073/pnas.1018081108 PubMedCentralPubMedGoogle Scholar
  83. Krishnamurthy H, Gouaux E (2012) X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature 481(7382):469–474. doi: 10.1038/nature10737 PubMedCentralPubMedGoogle Scholar
  84. Krishnamurthy H, Piscitelli CL, Gouaux E (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459(7245):347–355. doi: 10.1038/nature08143, nature08143 [pii]PubMedGoogle Scholar
  85. Krivov GG, Shapovalov MV, Dunbrack RL Jr (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins 77(4):778–795. doi: 10.1002/prot.22488 PubMedCentralPubMedGoogle Scholar
  86. Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13(6):472–482. doi: 10.1016/j.ccr.2008.05.005 PubMedGoogle Scholar
  87. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157(1):105–132PubMedGoogle Scholar
  88. Laskowski RA, Moss DS, Thornton JM (1993) Main-chain bond lengths and bond angles in protein structures. J Mol Biol 231(4):1049–1067. doi: 10.1006/jmbi.1993.1351 PubMedGoogle Scholar
  89. Lindahl E, Sansom MS (2008) Membrane proteins: molecular dynamics simulations. Curr Opin Struct Biol 18(4):425–431. doi: 10.1016/ PubMedGoogle Scholar
  90. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78(8):1950–1958. doi: 10.1002/prot.22711 PubMedCentralPubMedGoogle Scholar
  91. Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI (2006) OPM: orientations of proteins in membranes database. Bioinformatics 22(5):623–625. doi: 10.1093/bioinformatics/btk023, btk023 [pii]PubMedGoogle Scholar
  92. Lomize MA, Pogozheva ID, Joo H, Mosberg HI, Lomize AL (2012) OPM database and PPM web server: resources for positioning of proteins in membranes. Nucleic Acids Res 40(Database issue):D370–D376. doi: 10.1093/nar/gkr703 PubMedCentralPubMedGoogle Scholar
  93. Lorber DM, Shoichet BK (1998) Flexible ligand docking using conformational ensembles. Protein Sci 7(4):938–950. doi: 10.1002/pro.5560070411 PubMedCentralPubMedGoogle Scholar
  94. Lu F, Li S, Jiang Y, Jiang J, Fan H, Lu G, Deng D, Dang S, Zhang X, Wang J, Yan N (2011) Structure and mechanism of the uracil transporter UraA. Nature 472(7342):243–246. doi: 10.1038/nature09885 PubMedGoogle Scholar
  95. Ma D, Lu P, Yan C, Fan C, Yin P, Wang J, Shi Y (2012) Structure and mechanism of a glutamate–GABA antiporter. Nature 483(7391):632–636. doi: 10.1038/nature10917 PubMedGoogle Scholar
  96. Madej MG, Dang S, Yan N, Kaback HR (2013) Evolutionary mix-and-match with MFS transporters. Proc Natl Acad Sci U S A 110(15):5870–5874. doi: 10.1073/pnas.1303538110 PubMedCentralPubMedGoogle Scholar
  97. Madej MG, Soro SN, Kaback HR (2012) Apo-intermediate in the transport cycle of lactose permease (LacY). Proc Natl Acad Sci U S A 109(44):E2970–E2978. doi: 10.1073/pnas.1211183109 PubMedCentralPubMedGoogle Scholar
  98. Madhusudhan MS, Webb BM, Marti-Renom MA, Eswar N, Sali A (2009) Alignment of multiple protein structures based on sequence and structure features. Protein Eng Des Sel 22(9):569–574. doi: 10.1093/protein/gzp040, gzp040 [pii]PubMedCentralPubMedGoogle Scholar
  99. Madsen KK, White HS, Schousboe A (2010) Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther 125(3):394–401. doi: 10.1016/j.pharmthera.2009.11.007 PubMedGoogle Scholar
  100. Marks DS, Colwell LJ, Sheridan R, Hopf TA, Pagnani A, Zecchina R, Sander C (2011) Protein 3D structure computed from evolutionary sequence variation. PLoS One 6(12):e28766. doi: 10.1371/journal.pone.0028766 PubMedCentralPubMedGoogle Scholar
  101. Marti-Renom MA, Stuart AC, Fiser A, Sanchez R, Melo F, Sali A (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291–325. doi: 10.1146/annurev.biophys.29.1.291 PubMedGoogle Scholar
  102. Meiler J, Baker D (2006) ROSETTALIGAND: protein-small molecule docking with full side-chain flexibility. Proteins 65(3):538–548. doi: 10.1002/prot.21086 PubMedGoogle Scholar
  103. Melo F, Sanchez R, Sali A (2002) Statistical potentials for fold assessment. Protein Sci 11(2):430–448PubMedCentralPubMedGoogle Scholar
  104. Murzin AG, Brenner SE, Hubbard T, Chothia C (1995) SCOP: a structural classification of proteins database for the investigation of sequences and structures. J Mol Biol 247(4):536–540. doi: 10.1006/jmbi.1995.0159, S0022283685701593 [pii]PubMedGoogle Scholar
  105. Mysinger MM, Shoichet BK (2010) Rapid context-dependent ligand desolvation in molecular docking. J Chem Inf Model 50(9):1561–1573. doi: 10.1021/ci100214a PubMedGoogle Scholar
  106. Nakashita M, Sasaki K, Sakai N, Saito N (1997) Effects of tricyclic and tetracyclic antidepressants on the three subtypes of GABA transporter. Neurosci Res 29(1):87–91PubMedGoogle Scholar
  107. Newstead S, Drew D, Cameron AD, Postis VL, Xia X, Fowler PW, Ingram JC, Carpenter EP, Sansom MS, McPherson MJ, Baldwin SA, Iwata S (2011) Crystal structure of a prokaryotic homologue of the mammalian oligopeptide–proton symporters, PepT1 and PepT2. EMBO J 30(2):417–426. doi: 10.1038/emboj.2010.309 PubMedCentralPubMedGoogle Scholar
  108. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136(3):521–534. doi: 10.1016/j.cell.2008.11.044 PubMedCentralPubMedGoogle Scholar
  109. Nugent T, Jones DT (2009) Transmembrane protein topology prediction using support vector machines. BMC Bioinforma 10:159. doi: 10.1186/1471-2105-10-159 Google Scholar
  110. Nugent T, Jones DT (2010) Predicting transmembrane helix packing arrangements using residue contacts and a force-directed algorithm. PLoS Comput Biol 6(3):e1000714. doi: 10.1371/journal.pcbi.1000714 PubMedCentralPubMedGoogle Scholar
  111. Nugent T, Jones DT (2012) Membrane protein structural bioinformatics. J Struct Biol 179(3):327–337. doi: 10.1016/j.jsb.2011.10.008 PubMedGoogle Scholar
  112. Nyola A, Karpowich NK, Zhen J, Marden J, Reith ME, Wang DN (2010) Substrate and drug binding sites in LeuT. Curr Opin Struct Biol 20(4):415–422. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  113. O’Dwyer PJ, Alonso MT, Leyland-Jones B (1984) Acivicin: a new glutamine antagonist in clinical trials. J Clin Oncol 2(9):1064–1071PubMedGoogle Scholar
  114. Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350(6316):350–354. doi: 10.1038/350350a0 PubMedGoogle Scholar
  115. Paczkowski FA, Bonisch H, Bryan-Lluka LJ (2002) Pharmacological properties of the naturally occurring Ala(457)Pro variant of the human norepinephrine transporter. Pharmacogenetics 12(2):165–173PubMedGoogle Scholar
  116. Pedersen BP, Kumar H, Waight AB, Risenmay AJ, Roe-Zurz Z, Chau BH, Schlessinger A, Bonomi M, Harries W, Sali A, Johri AK, Stroud RM (2013) Crystal structure of a eukaryotic phosphate transporter. Nature. doi: 10.1038/nature12042 Google Scholar
  117. Pei J, Kim BH, Grishin NV (2008) PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic Acids Res 36(7):2295–2300. doi: 10.1093/nar/gkn072 PubMedCentralPubMedGoogle Scholar
  118. Perez C, Ziegler C (2013) Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. Biol Chem. doi: 10.1515/hsz-2012-0336 PubMedGoogle Scholar
  119. Petrascheck M, Ye X, Buck LB (2007) An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature 450(7169):553–556. doi: 10.1038/nature05991, nature05991 [pii]PubMedGoogle Scholar
  120. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612. doi: 10.1002/jcc.20084 PubMedGoogle Scholar
  121. Pieper U, Schlessinger A, Kloppmann E, Chang GA, Chou JJ, Dumont ME, Fox BG, Fromme P, Hendrickson WA, Malkowski MG, Rees DC, Stokes DL, Stowell MH, Wiener MC, Rost B, Stroud RM, Stevens RC, Sali A (2013) Coordinating the impact of structural genomics on the human alpha-helical transmembrane proteome. Nat Struct Mol Biol 20(2):135–138. doi: 10.1038/nsmb.2508 PubMedCentralPubMedGoogle Scholar
  122. Pieper U, Webb BM, Barkan DT, Schneidman-Duhovny D, Schlessinger A, Braberg H, Yang Z, Meng EC, Pettersen EF, Huang CC, Datta RS, Sampathkumar P, Madhusudhan MS, Sjolander K, Ferrin TE, Burley SK, Sali A (2011) ModBase, a database of annotated comparative protein structure models, and associated resources. Nucleic Acids Res 39(Database issue):D465–D474. doi: 10.1093/nar/gkq1091 PubMedCentralPubMedGoogle Scholar
  123. Pirovano W, Feenstra KA, Heringa J (2008) PRALINETM: a strategy for improved multiple alignment of transmembrane proteins. Bioinformatics 24(4):492–497. doi: 10.1093/bioinformatics/btm636 PubMedGoogle Scholar
  124. Povey S, Lovering R, Bruford E, Wright M, Lush M, Wain H (2001) The HUGO gene nomenclature committee (HGNC). Hum Genet 109(6):678–680. doi: 10.1007/s00439-001-0615-0 PubMedGoogle Scholar
  125. Punta M, Forrest LR, Bigelow H, Kernytsky A, Liu J, Rost B (2007) Membrane protein prediction methods. Methods 41(4):460–474. doi: 10.1016/j.ymeth.2006.07.026 PubMedCentralPubMedGoogle Scholar
  126. Radestock S, Forrest LR (2011) The alternating-access mechanism of MFS transporters arises from inverted-topology repeats. J Mol Biol 407(5):698–715. doi: 10.1016/j.jmb.2011.02.008 PubMedGoogle Scholar
  127. Ressl S, Terwisscha van Scheltinga AC, Vonrhein C, Ott V, Ziegler C (2009) Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP. Nature 458(7234):47–52. doi: 10.1038/nature07819, nature07819 [pii]PubMedGoogle Scholar
  128. Roberts LM, Black DS, Raman C, Woodford K, Zhou M, Haggerty JE, Yan AT, Cwirla SE, Grindstaff KK (2008) Subcellular localization of transporters along the rat blood–brain barrier and blood–cerebral-spinal fluid barrier by in vivo biotinylation. Neuroscience 155(2):423–438. doi: 10.1016/j.neuroscience.2008.06.015 PubMedGoogle Scholar
  129. Rohl CA, Strauss CE, Misura KM, Baker D (2004) Protein structure prediction using Rosetta. Methods Enzymol 383:66–93. doi: 10.1016/S0076-6879(04)83004-0 PubMedGoogle Scholar
  130. Rost B, Casadio R, Fariselli P, Sander C (1995) Transmembrane helices predicted at 95 % accuracy. Protein Sci 4(3):521–533PubMedCentralPubMedGoogle Scholar
  131. Rost B, Liu J, Nair R, Wrzeszczynski KO, Ofran Y (2003) Automatic prediction of protein function. Cell Mol Life Sci 60(12):2637–2650. doi: 10.1007/s00018-003-3114-8 PubMedGoogle Scholar
  132. Runkel F, Bruss M, Nothen MM, Stober G, Propping P, Bonisch H (2000) Pharmacological properties of naturally occurring variants of the human norepinephrine transporter. Pharmacogenetics 10(5):397–405PubMedGoogle Scholar
  133. Russel D, Lasker K, Webb B, Velazquez-Muriel J, Tjioe E, Schneidman-Duhovny D, Peterson B, Sali A (2012) Putting the pieces together: integrative modeling platform software for structure determination of macromolecular assemblies. PLoS Biol 10(1):e1001244. doi: 10.1371/journal.pbio.1001244 PubMedCentralPubMedGoogle Scholar
  134. Saier MH Jr (2000) A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol Mol Biol Rev 64(2):354–411PubMedCentralPubMedGoogle Scholar
  135. Saier MH Jr, Yen MR, Noto K, Tamang DG, Elkan C (2009) The transporter classification database: recent advances. Nucleic Acids Res 37(Database issue):D274–D278. doi: 10.1093/nar/gkn862, doi:gkn862 [pii]PubMedCentralPubMedGoogle Scholar
  136. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815PubMedGoogle Scholar
  137. Sanchez R, Sali A (1998) Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. Proc Natl Acad Sci U S A 95(23):13597–13602PubMedCentralPubMedGoogle Scholar
  138. Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, Giacomini KM, Sali A (2011) Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc Natl Acad Sci U S A 108(38):15810–15815. doi: 10.1073/pnas.1106030108 PubMedCentralPubMedGoogle Scholar
  139. Schlessinger A, Khuri N, Giacomini KM, Sali A (2013a) Molecular modeling and ligand docking for solute carrier (SLC) transporters. Curr Top Med Chem 13(7):843–856PubMedGoogle Scholar
  140. Schlessinger A, Matsson P, Shima JE, Pieper U, Yee SW, Kelly L, Apeltsin L, Stroud RM, Ferrin TE, Giacomini KM, Sali A (2010) Comparison of human solute carriers. Protein Sci 19(3):412–428. doi: 10.1002/pro.320 PubMedCentralPubMedGoogle Scholar
  141. Schlessinger A, Wittwer MB, Dahlin A, Khuri N, Bonomi M, Fan H, Giacomini KM, Sali A (2012) High selectivity of the gamma-aminobutyric acid transporter 2 (GAT-2, SLC6A13) revealed by structure-based approach. J Biol Chem 287(45):37745–37756. doi: 10.1074/jbc.M112.388157 PubMedCentralPubMedGoogle Scholar
  142. Schlessinger A, Yee SW, Sali A, Giacomini KM (2013) SLC classification: an update. Clin Pharmacol Ther 94(1):19–23. doi: 10.1038/clpt.2013.73 PubMedGoogle Scholar
  143. Schulze S, Koster S, Geldmacher U, Terwisscha van Scheltinga AC, Kuhlbrandt W (2010) Structural basis of Na(+)-independent and cooperative substrate/product antiport in CaiT. Nature 467(7312):233–236. doi: 10.1038/nature09310 PubMedGoogle Scholar
  144. Schushan M, Rimon A, Haliloglu T, Forrest LR, Padan E, Ben-Tal N (2012) A model-structure of a periplasm-facing state of the NhaA antiporter suggests the molecular underpinnings of pH-induced conformational changes. J Biol Chem 287(22):18249–18261. doi: 10.1074/jbc.M111.336446 PubMedCentralPubMedGoogle Scholar
  145. Severinsen K, Kraft JF, Koldso H, Vinberg KA, Rothman RB, Partilla JS, Wiborg O, Blough B, Schiott B, Sinning S (2012) Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters. ACS Chem Neurosci 3(9):693–705. doi: 10.1021/cn300040f PubMedCentralPubMedGoogle Scholar
  146. Shaffer PL, Goehring A, Shankaranarayanan A, Gouaux E (2009) Structure and mechanism of a Na+-independent amino acid transporter. Science 325(5943):1010–1014. doi: 10.1126/science.1176088, 1176088 [pii]PubMedCentralPubMedGoogle Scholar
  147. Shaw DE, Maragakis P, Lindorff-Larsen K, Piana S, Dror RO, Eastwood MP, Bank JA, Jumper JM, Salmon JK, Shan Y, Wriggers W (2010) Atomic-level characterization of the structural dynamics of proteins. Science 330(6002):341–346. doi: 10.1126/science.1187409 PubMedGoogle Scholar
  148. Shen MY, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15(11):2507–2524PubMedCentralPubMedGoogle Scholar
  149. Shi L, Quick M, Zhao Y, Weinstein H, Javitch JA (2008) The mechanism of a neurotransmitter:sodium symporter—inward release of Na+ and substrate is triggered by substrate in a second binding site. Mol Cell 30(6):667–677. doi: 10.1016/j.molcel.2008.05.008, S1097-2765(08)00359-6 [pii]PubMedCentralPubMedGoogle Scholar
  150. Shi L, Weinstein H (2010) Conformational rearrangements to the intracellular open states of the LeuT and ApcT transporters are modulated by common mechanisms. Biophys J 99(12):L103–L105. doi: 10.1016/j.bpj.2010.10.003 PubMedCentralPubMedGoogle Scholar
  151. Shoichet BK (2004) Virtual screening of chemical libraries. Nature 432(7019):862–865PubMedCentralPubMedGoogle Scholar
  152. Shoichet BK, Kobilka BK (2012) Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol Sci 33(5):268–272. doi: 10.1016/ PubMedCentralPubMedGoogle Scholar
  153. Shoichet BK, Stroud RM, Santi DV, Kuntz ID, Perry KM (1993) Structure-based discovery of inhibitors of thymidylate synthase. Science 259(5100):1445–1450PubMedGoogle Scholar
  154. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM (2008) Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83(2):273–280. doi: 10.1038/sj.clpt.6100275, 6100275 [pii]PubMedCentralPubMedGoogle Scholar
  155. Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, Ferrin TE, Herskowitz I, Giacomini KM (2003) Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci U S A 100(10):5902–5907. doi: 10.1073/pnas.0730858100, 0730858100 [pii]PubMedCentralPubMedGoogle Scholar
  156. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117(5):1422–1431PubMedCentralPubMedGoogle Scholar
  157. Singh SK, Piscitelli CL, Yamashita A, Gouaux E (2008) A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322(5908):1655–1661. doi: 10.1126/science.1166777, 322/5908/1655 [pii]PubMedCentralPubMedGoogle Scholar
  158. Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448(7156):952–956PubMedGoogle Scholar
  159. Smith DE, Clemencon B, Hediger MA (2013) Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Aspects Med 34(2–3):323–336. doi: 10.1016/j.mam.2012.11.003 PubMedGoogle Scholar
  160. Soding J, Biegert A, Lupas AN (2005) The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res 33(Web Server issue):W244–W248. doi: 10.1093/nar/gki408 PubMedCentralPubMedGoogle Scholar
  161. Sonnhammer EL, von Heijne G, Krogh A (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. Proc Int Conf Intell Syst Mol Biol 6:175–182PubMedGoogle Scholar
  162. Soto CS, Fasnacht M, Zhu J, Forrest L, Honig B (2008) Loop modeling: sampling, filtering, and scoring. Proteins 70(3):834–843. doi: 10.1002/prot.21612 PubMedCentralPubMedGoogle Scholar
  163. Sperandio O, Miteva MA, Delfaud F, Villoutreix BO (2006) Receptor-based computational screening of compound databases: the main docking-scoring engines. Curr Protein Pept Sci 7(5):369–393PubMedGoogle Scholar
  164. Stamm M, Staritzbichler R, Khafizov K, Forrest LR (2013) Alignment of helical membrane protein sequences using alignme. PLoS One 8(3):e57731. doi: 10.1371/journal.pone.0057731 PubMedCentralPubMedGoogle Scholar
  165. Traynor K (2013) Canagliflozin approved for type 2 diabetes. Am J Health Syst Pharm 70(10):834. doi: 10.2146/news130035 Google Scholar
  166. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461. doi: 10.1002/jcc.21334 PubMedCentralPubMedGoogle Scholar
  167. Tsirigos KD, Hennerdal A, Kall L, Elofsson A (2012) A guideline to proteome-wide alpha-helical membrane protein topology predictions. Proteomics 12(14):2282–2294. doi: 10.1002/pmic.201100495 PubMedGoogle Scholar
  168. Tusnady GE, Dosztanyi Z, Simon I (2005) TMDET: web server for detecting transmembrane regions of proteins by using their 3D coordinates. Bioinformatics 21(7):1276–1277. doi: 10.1093/bioinformatics/bti121 PubMedGoogle Scholar
  169. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi: 10.1126/science.1160809 PubMedCentralPubMedGoogle Scholar
  170. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein–ligand docking using GOLD. Proteins 52(4):609–623. doi: 10.1002/prot.10465 PubMedGoogle Scholar
  171. Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447(5):532–542. doi: 10.1007/s00424-003-1086-z PubMedGoogle Scholar
  172. Wang Y, Welty DF (1996) The simultaneous estimation of the influx and efflux blood–brain barrier permeabilities of gabapentin using a microdialysis-pharmacokinetic approach. Pharm Res 13(3):398–403PubMedGoogle Scholar
  173. Watanabe A, Choe S, Chaptal V, Rosenberg JM, Wright EM, Grabe M, Abramson J (2010) The mechanism of sodium and substrate release from the binding pocket of vSGLT. Nature 468(7326):988–991. doi: 10.1038/nature09580 PubMedCentralPubMedGoogle Scholar
  174. Weyand S, Shimamura T, Yajima S, Suzuki S, Mirza O, Krusong K, Carpenter EP, Rutherford NG, Hadden JM, O’Reilly J, Ma P, Saidijam M, Patching SG, Hope RJ, Norbertczak HT, Roach PC, Iwata S, Henderson PJ, Cameron AD (2008) Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science 322(5902):709–713. doi: 10.1126/science.1164440, 1164440 [pii]PubMedCentralPubMedGoogle Scholar
  175. Wise DR, Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8):427–433. doi: 10.1016/j.tibs.2010.05.003 PubMedCentralPubMedGoogle Scholar
  176. Xiang Z, Steinbach PJ, Jacobson MP, Friesner RA, Honig B (2007) Prediction of side-chain conformations on protein surfaces. Proteins 66(4):814–823. doi: 10.1002/prot.21099 PubMedCentralPubMedGoogle Scholar
  177. Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E (2005) Crystal structure of a bacterial homologue of Na+/Cl dependent neurotransmitter transporters. Nature 437(7056):215–223PubMedGoogle Scholar
  178. Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62(4):1010–1025. doi: 10.1002/prot.20817 PubMedCentralPubMedGoogle Scholar
  179. Yernool D, Boudker O, Jin Y, Gouaux E (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431(7010):811–818PubMedGoogle Scholar
  180. Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM (2012) Highlights from the international transporter consortium second workshop. Clin Pharmacol Ther 92(5):553–556. doi: 10.1038/clpt.2012.126 PubMedGoogle Scholar
  181. Zemla A, Venclovas C, Moult J, Fidelis K (1999) Processing and analysis of CASP3 protein structure predictions. Proteins Suppl 3:22–29PubMedGoogle Scholar
  182. Zhao Y, Terry D, Shi L, Weinstein H, Blanchard SC, Javitch JA (2010) Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature 465(7295):188–193. doi: 10.1038/nature09057 PubMedCentralPubMedGoogle Scholar
  183. Zhao Y, Terry DS, Shi L, Quick M, Weinstein H, Blanchard SC, Javitch JA (2011) Substrate-modulated gating dynamics in a Na(+)-coupled neurotransmitter transporter homologue. Nature. doi: 10.1038/nature09971 Google Scholar

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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Pharmacology and Systems TherapeuticsIcahn School of Medicine at Mount SinaiNew YorkUSA

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