Skip to main content
SpringerLink
Log in

Homology Modeling of Transporter Proteins (Carriers and Ion Channels)

  • Protocol
  • First Online:
Homology Modeling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 857))

Abstract

Transporter proteins are divided into channels and carriers and constitute families of membrane proteins of physiological and pharmacological importance. These proteins are targeted by several currently prescribed drugs, and they have a large potential as targets for new drug development. Ion channels and carriers are difficult to express and purify in amounts for X-ray crystallography and nuclear magnetic resonance (NMR) studies, and few carrier and ion channel structures are deposited in the PDB database. The scarcity of atomic resolution 3D structures of carriers and channels is a problem for understanding their molecular mechanisms of action and for designing new compounds with therapeutic potentials. The homology modeling approach is a valuable approach for obtaining structural information about carriers and ion channels when no crystal structure of the protein of interest is available. In this chapter, computational approaches for constructing homology models of carriers and transporters are reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Landry Y, Gies JP (2008) Drugs and their molecular targets: An updated overview. Fundam Clin Pharmacol 22:1–18

    Article  PubMed  CAS  Google Scholar 

  2. 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 Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236

    Google Scholar 

  3. Saier MH, Jr. (2000) A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol Mol Biol Rev 64:354–411

    Article  PubMed  CAS  Google Scholar 

  4. Rang HP, Dale MM, Ritter JM, Morre PK (2003) Pharmacology. 5th edn. Churchill Livingstone, ISBN-10 / ASIN: 0443071454

    Google Scholar 

  5. Caffrey M (2003) Membrane protein crystallization. J Struct Biol 142:108–132

    Article  PubMed  CAS  Google Scholar 

  6. Cherezov V, Clogston J, Papiz MZ, Caffrey M (2006) Room to move: Crystallizing membrane proteins in swollen lipidic mesophases. J Mol Biol 357:1605–1618

    Article  PubMed  CAS  Google Scholar 

  7. Cherezov V, Peddi A, Muthusubramaniam L, Zheng YF, Caffrey M (2004) A robotic system for crystallizing membrane and soluble proteins in lipidic mesophases. Acta Crystallogr D Biol Crystallogr 60:1795–1807

    Article  PubMed  Google Scholar 

  8. Frishman D, Mewes HW (1997) Protein structural classes in five complete genomes. Nat Struct Biol 4:626–628

    Article  PubMed  CAS  Google Scholar 

  9. Wallin E, von Heijne G (1998) Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci 7:1029–1038

    Article  PubMed  CAS  Google Scholar 

  10. Bradley P, Misura KM, Baker D (2005) Toward high-resolution de novo structure prediction for small proteins. Science 309:1868–1871

    Article  PubMed  CAS  Google Scholar 

  11. Casadio R, Fariselli P, Martelli PL, Tasco G (2007) Thinking the impossible: How to solve the protein folding problem with and without homologous structures and more. Methods Mol Biol 350:305–320

    PubMed  CAS  Google Scholar 

  12. Forrest LR, Tang CL, Honig B (2006) On the accuracy of homology modeling and sequence alignment methods applied to membrane proteins. Biophys J 91:508–517

    Article  PubMed  CAS  Google Scholar 

  13. Eddy SR (1998) Profile hidden markov models. Bioinformatics 14:755–763

    Article  PubMed  CAS  Google Scholar 

  14. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped blast and psi-blast: A new generation of protein database search programs. Nucleic Acids Res 25:3389–3402

    Article  PubMed  CAS  Google Scholar 

  15. Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of p-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722

    Article  PubMed  CAS  Google Scholar 

  16. Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug abc transporter. Nature

    Google Scholar 

  17. Yamashita A, Singh SK, Kawate T, Jin Y, Gouaux E (2005) Crystal structure of a bacterial homologue of na+/cl--dependent neurotransmitter transporters. Nature 437:215–223

    Article  PubMed  CAS  Google Scholar 

  18. Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S (2003) Structure and mechanism of the lactose permease of escherichia coli. Science 301:610–615

    Article  PubMed  CAS  Google Scholar 

  19. Ravna AW, Sager G, Dahl SG, Sylte I (2009) Membrane transporters: Structure, function and targets for drug design. In: Napier S, Bingham M (eds) Transporters as targets for drugs vol 4. Topics in medicinal chemistry pp 15–51.

    Google Scholar 

  20. Tai K, Fowler P, Mokrab Y, Stansfeld P, Sansom MS (2008) Molecular modeling and simulation studies of ion channel structures, dynamics and mechanisms. Methods Cell Biol 90:233–265

    Article  PubMed  CAS  Google Scholar 

  21. Frydenvang K, Lash LL, Naur P, Postila PA, Pickering DS, Smith CM, Gajhede M, Sasaki M, Sakai R, Pentikainen OT, Swanson GT, Kastrup JS (2009) Full domain closure of the ligand-binding core of the ionotropic glutamate receptor iglur5 induced by the high affinity agonist dysiherbaine and the functional antagonist 8,9-dideoxyneodysiherbaine. J Biol Chem 284:14219–14229

    Article  PubMed  CAS  Google Scholar 

  22. Hibbs RE, Sulzenbacher G, Shi J, Talley TT, Conrod S, Kem WR, Taylor P, Marchot P, Bourne Y (2009) Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor. EMBO J 28:3040–3051

    Article  PubMed  CAS  Google Scholar 

  23. Wieman H, Tondel K, Anderssen E, Drablos F (2004) Homology-based modelling of targets for rational drug design. Mini Rev Med Chem 4:793–804

    PubMed  CAS  Google Scholar 

  24. Abagyan R, Totrov M, Kuznetsov DN (1994) Icm - a new method for protein modeling and design. Applications to docking and structure prediction from the distorted native comformation. J Comp Chem 15:488–506

    Article  CAS  Google Scholar 

  25. Vriend G (1990) What if: A molecular modeling and drug design program. J Mol Graph 8:52–56, 29

    Google Scholar 

  26. Levitt M (1992) Accurate modeling of protein conformation by automatic segment matching. J Mol Biol 226:507–533

    Article  PubMed  CAS  Google Scholar 

  27. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815

    Article  PubMed  CAS  Google Scholar 

  28. Laskoswki RA, MacArthur MW, Moss DS, Thorton JM (1993) Procheck: A program to check the stereochemical quality of protein structures. J Appl Cryst 26:283–291

    Article  Google Scholar 

  29. Hooft RW, Vriend G, Sander C, Abola EE (1996) Errors in protein structures. Nature 381:272

    Article  PubMed  CAS  Google Scholar 

  30. Kryshtafovych A, Venclovas C, Fidelis K, Moult J (2005) Progress over the first decade of casp experiments. Proteins 61 Suppl 7:225–236

    Article  PubMed  CAS  Google Scholar 

  31. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) High-resolution crystal structure of an engineered human beta2-adrenergic g protein-coupled receptor. Science 318:1258–1265

    Article  PubMed  CAS  Google Scholar 

  32. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Crystal structure of rhodopsin: A g protein-coupled receptor. Science 289:739–745

    Article  PubMed  CAS  Google Scholar 

  33. Kaback HR, Wu J (1997) From membrane to molecule to the third amino acid from the left with a membrane transport protein. Q Rev Biophys 30:333–364

    Article  PubMed  CAS  Google Scholar 

  34. Ward A, Reyes CL, Yu J, Roth CB, Chang G (2007) Flexibility in the abc transporter msba: Alternating access with a twist. Proc Natl Acad Sci U S A 104:19005–19010

    Article  PubMed  CAS  Google Scholar 

  35. Higgins CF, Linton KJ (2001) Structural biology. The xyz of abc transporters. Science 293:1782–1784

    Article  PubMed  CAS  Google Scholar 

  36. Oswald C, Holland IB, L. S (2006) The motor domains of abc-transporters - what can structures tell us? Naunyn-Schmiedeberg’s Arch Pharmacol 372:385–399

    Google Scholar 

  37. Ravna AW, Sylte I, Sager G (2007) Molecular model of the outward facing state of the human p-glycoprotein (abcb1), and comparison to a model of the human mrp5 (abcc5). Theor Biol Med Model 4:33

    Article  PubMed  Google Scholar 

  38. Ravna AW, Sager G (2008) Molecular model of the outward facing state of the human multidrug resistance protein 4 (mrp4/abcc4). Bioorg Med Chem Lett 18:3481–3483

    Article  PubMed  CAS  Google Scholar 

  39. Ravna AW, Sylte I, Sager G (2008) A molecular model of a putative substrate releasing conformation of multidrug resistance protein 5 (mrp5). Eur J Med Chem 43:2557–2567

    Article  PubMed  CAS  Google Scholar 

  40. Ravna AW, Sylte I, Sager G (2009) Binding site of abc transporter homology models confirmed by abcb1 crystal structure. Theor Biol Med Model 6:20

    Article  PubMed  Google Scholar 

  41. Loo TW, Bartlett MC, Clarke DM (2003) Methanethiosulfonate derivatives of rhodamine and verapamil activate human p-glycoprotein at different sites. J Biol Chem 278:50136–50141

    Article  PubMed  CAS  Google Scholar 

  42. Loo TW, Bartlett MC, Clarke DM (2006) Transmembrane segment 1 of human p-glycoprotein contributes to the drug-binding pocket. Biochem J 396:537–545

    Article  PubMed  CAS  Google Scholar 

  43. Loo TW, Bartlett MC, Clarke DM (2006) Transmembrane segment 7 of human p-glycoprotein forms part of the drug-binding pocket. Biochem J

    Google Scholar 

  44. Loo TW, Clarke DM (2002) Location of the rhodamine-binding site in the human multidrug resistance p-glycoprotein. J Biol Chem 277:44332–44338

    Article  PubMed  CAS  Google Scholar 

  45. Loo TW, Clarke DM (2005) Recent progress in understanding the mechanism of p-glycoprotein-mediated drug efflux. J Membr Biol 206:173–185

    Article  PubMed  CAS  Google Scholar 

  46. Muller M, Mayer R, Hero U, Keppler D (1994) Atp-dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 p-glycoprotein. FEBS Lett 343:168–172

    Article  PubMed  CAS  Google Scholar 

  47. Orlowski S, Garrigos M (1999) Multiple recognition of various amphiphilic molecules by the multidrug resistance p-glycoprotein: Molecular mechanisms and pharmacological consequences coming from functional interactions between various drugs. Anticancer Res 19:3109–3123

    PubMed  CAS  Google Scholar 

  48. Smit JW, Duin E, Steen H, Oosting R, Roggeveld J, Meijer DK (1998) Interactions between p-glycoprotein substrates and other cationic drugs at the hepatic excretory level. Br J Pharmacol 123:361–370

    Article  PubMed  CAS  Google Scholar 

  49. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW (2002) Interaction of common azole antifungals with p glycoprotein. Antimicrob Agents Chemother 46:160–165

    Article  PubMed  CAS  Google Scholar 

  50. Borst P, de Wolf C, van de Wetering K (2007) Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453:661–673

    Article  PubMed  CAS  Google Scholar 

  51. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258

    Article  PubMed  CAS  Google Scholar 

  52. 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

    Google Scholar 

  53. Ravna AW, Sylte I, Dahl SG (2009) Structure and localisation of drug binding sites on neurotransmitter transporters. J Mol Model

    Google Scholar 

  54. Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956

    Article  PubMed  CAS  Google Scholar 

  55. Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN (2007) Leut-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317:1390–1393

    Article  PubMed  CAS  Google Scholar 

  56. Kitayama S, Shimada S, Xu H, Markham L, Donovan DM, Uhl GR (1992) Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. Proc Natl Acad Sci U S A 89:7782–7785

    Article  PubMed  CAS  Google Scholar 

  57. Lee SH, Chang MY, Lee KH, Park BS, Lee YS, Chin HR, Lee YS (2000) Importance of valine at position 152 for the substrate transport and 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane binding of dopamine transporter. Mol Pharmacol 57:883–889

    PubMed  CAS  Google Scholar 

  58. Chen JG, Sachpatzidis A, Rudnick G (1997) The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. J Biol Chem 272:28321–28327

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The molecular modeling group, at the Department of Medical Biology, University of Tromsø, acknowledges the financial support from the Polish-Norwegian Research Fund, the Norwegian Cancer Society, the Research Council of Norway, and the University of Tromsø.

Author information

Authors and Affiliations

  1. Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

    Aina Westrheim Ravna & Ingebrigt Sylte

Authors
  1. Aina Westrheim Ravna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingebrigt Sylte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ingebrigt Sylte .

Editor information

Editors and Affiliations

  1. Molsoft L.L.C., Sorrento Valley Road 11199, S209 San Diego, 92121, California, USA

    Andrew J. W. Orry

  2. Skaggs School of Pharmacy &, Pharmaceutical Sciences, University of California, San Diego, Gilman Drive 9500, La Jolla, 92093, California, USA

    Ruben Abagyan

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media,LLC

About this protocol

Cite this protocol

Ravna, A.W., Sylte, I. (2011). Homology Modeling of Transporter Proteins (Carriers and Ion Channels). In: Orry, A., Abagyan, R. (eds) Homology Modeling. Methods in Molecular Biology, vol 857. Humana Press. https://doi.org/10.1007/978-1-61779-588-6_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-588-6_12

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-587-9

  • Online ISBN: 978-1-61779-588-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation