AAPS PharmSci

, Volume 1, Issue 2, pp 7–26 | Cite as

The venus flytrap of periplasmic binding proteins: An ancient protein module present in multiple drug receptors

  • Christian B. Felder
  • Richard C. Graul
  • Alan Y. Lee
  • Hans-Peter Merkle
  • Wolfgang Sadee


Located between the inner and outer membranes of Gram-negative bacteria, periplasmic binding proteins (PBPs) scavenge or sense diverse nutrients in the environment by coupling to transporters or chemotaxis receptors in the inner membrane. Their three-dimensional structures have been deduced in atomic detail with the use of X-ray crystallography, both in the free and liganded state. PBPs consist of two large lobes that close around the bound ligand, resembling a Venus flytrap. This architecture is reiterated in transcriptional regulators, such as the lac repressors. In the process of evolution, genes encoding the PBPs have fused with genes for integral membrane proteins. Thus, diverse mammalian receptors contain extracellular ligand binding domains that are homologous to the PBPs; these include glutamate/glycine-gated ion channels such as the NMDA receptor, G protein-coupled receptors, including metabotropic glutamate, GABA-B, calcium sensing, and pheromone receptors, and atrial natriuretic peptide-guanylate cyclase receptors. Many of these receptors are promising drug targets. On the basis of homology to PBPs and a recently resolved crystal structure of the extracellular binding domain of a glutamate receptor ion channel, it is possible to construct three-dimensional models of their ligand binding domains. Together with the extensive information available on the mechanism of ligand binding to PBPs, such models can serve as a guide in drug discovery.


Glutamate Atrial Natriuretic Peptide Guanylate Cyclase Metabotropic Glutamate Receptor GABAB Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Bork P, Downing AK, Kieffer B, Campbell ID. Structure and distribution of modules in extracellular proteins. Q. Rev. Biophys. 1996;29:119–167.PubMedCrossRefGoogle Scholar
  2. 2.
    Quiocho FA, Ledvina PS. Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes. Mol. Microbiol. 1996;20:17–25.PubMedCrossRefGoogle Scholar
  3. 3.
    O’Hara PJ, Sheppard PO, Thogersen H. et al. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron 1993;11:41–52. [PUBMED]PubMedCrossRefGoogle Scholar
  4. 4.
    Laube B, Hirai H, Sturgess M, Betz H, Kuhse J. Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 1997;18:493–503.PubMedCrossRefGoogle Scholar
  5. 5.
    Nichols JC, Vyas NK, Quiocho FA, Matthews KS. Model of lactose repressor core based on alignment with sugar-binding proteins is concordant with genetic and chemical data. J. Biol. Chem. 1993;268:17602–17612.PubMedGoogle Scholar
  6. 6.
    Oh BH, Pandit J, Kang CH, Nikaido K, Gokcen S, Ames GF, Kim SH. Three-dimensional structures of the periplasmic lysine/arginine/omithine-binding protein with and without a ligand. J. Biol. Chem. 1993;268:11348–11355.PubMedGoogle Scholar
  7. 7.
    Conklin BR, Bourne HR. Homeostatic signals. Marriage of the flytrap and the serpent. Nature 1994;367:22.PubMedCrossRefGoogle Scholar
  8. 8.
    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J. Mol. Biol. 1990;215:403–410.PubMedCrossRefGoogle Scholar
  9. 9.
    Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389–3402.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Graul RC, Sadée W. Evolutionary relationships among proteins probed by an iterative neighborhood cluster analysis (INCA). Alignment of bacteriorhodopsins with the yeast sequence YR02. Pharm. Res. 1997;14:1533–1541.PubMedCrossRefGoogle Scholar
  11. 11.
    Richarme G, Caldas TD. Chaperone proterties of the bacterial periplasmic substrate-binding proteins. J. Biol. Chem. 1997;272:15607–15612.PubMedCrossRefGoogle Scholar
  12. 12.
    Schuler GD, Epstein JA, Onkawa H, Kans JA. Entrez: molecular biology database and retrieval system. Methods Enzymol. 1996;266:141–162.PubMedCrossRefGoogle Scholar
  13. 13.
    Higgins CF. ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 1992;8:67–113.PubMedCrossRefGoogle Scholar
  14. 14.
    Shilton BH, Flocco MM, Nilsson M, Mowbray SL. Conformational changes of three periplasmic receptors for bacterial chemotaxis and transport: the maltose-, glucose/galactose- and ribose-binding proteins. J. Mol. Biol. 1996;264:350–363.PubMedCrossRefGoogle Scholar
  15. 15.
    Wolf A, Lee KC, Kirsch JF, Ames GFL. Ligand-dependent conformational plasticity of the periplasmic histidine-binding protein HisJ. Involvement in transport specificity. J. Biol. Chem. 1996;271:21243–21250.PubMedCrossRefGoogle Scholar
  16. 16.
    Oh BH, Ames GF, Kim SH. Structural basis for multiple ligand specificity of the periplasmic lysine-, arginine-, ornithine-binding protein. J. Biol. Chem. 1994;269:26323–26330.PubMedGoogle Scholar
  17. 17.
    Oh BH, Kang CH, De Bondt H, Kim SH, Nikaido K, Joshi AK, Ames GF. The bacterial periplasmic histidine-binding protein structure/function analysis of the ligand-binding site and comparison with related proteins. J. Biol. Chem. 1994;269:4135–4143.PubMedGoogle Scholar
  18. 18.
    Tame JR, Murshudov GN, Dodson EJ, et al. The structural basis of sequence-independent peptide binding by OppA protein. Science 1994;264:1578–1581.PubMedCrossRefGoogle Scholar
  19. 19.
    Olah GA, Trakhanov S, Trewhella J, Quiocho FA. Leucine/isoleucine/valine-binding protein contracts upon binding of ligand. J. Biol. Chem. 1993;268:16241–16247.PubMedGoogle Scholar
  20. 20.
    Sack JS, Saper MA, Quiocho FA. Periplasmic binding protein structure and function. Refined X-ray structures of the leucine/isoleucine/valine-binding protein and its complex with leucine. J. Mol. Biol. 1989;206:171–191.PubMedCrossRefGoogle Scholar
  21. 21.
    Kempner ES. Movable lobes and flexible loops in proteins. Structural deformations that control biochemical activity. FEBS Lett. 1993;326:4–10.PubMedCrossRefGoogle Scholar
  22. 22.
    Higgin CF, Ames GF. Two periplasmic transport proteins which interact with a common membrane receptor show extensive homology: complete nucleotide sequences. Proc. Natl. Acad. Sci. U S A 1981;78:6038–6042.CrossRefGoogle Scholar
  23. 23.
    Gilson E, Alloing G, Schmidt T, Claverys JP, Dudler R, Hofnung M. Evidence for high affinity binding-protein dependent transport systems in gram-positive bacteria and in Mycoplasma. Embo J. 1988;7:3971–3974.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Yoshida K, Fujimura M, Yanai N, Fujita Y. Cloning and sequencing of a 23-kb region of the Bacillus subtilis genome between the iol and hut operons. DNA Res. 1995;2:295–301.PubMedCrossRefGoogle Scholar
  25. 25.
    Kronemeyer W, Peekhaus N, Kramer R, Sahm H, Eggeling L. Structure of the gluABCD cluster encoding the glutamate uptake system of Corynebacterium glutamicum. J. Bacteriol. 1995;177:1152–1158.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Turner MS, Timms P, Hafner LM, Giffard PM. Identification and characterization of a basic cell surface-located protein from lactobacillus fermentum BR11. J. Bacteriol. 1997;179:3310–3316.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Roos S, Aleljung P, Robert N, Lee B, Wadstrom T, Lindberg M, Jonsson H. A collagen binding protein from Lactobacillus reuteri is part of an ABC transporter system? FEMS Microbiol. Lett. 1996;144:33–38.PubMedCrossRefGoogle Scholar
  28. 28.
    Pei Z, Blaser MJ. PEB1, the major cell-binding factor of Campylobacter jejuni, is a homolog of the binding component in gramnegative nutrient transport systems. J. Biol. Chem. 1993;268:18717–18725.PubMedGoogle Scholar
  29. 29.
    Bowie JU, Luthy R, Eisenberg D. A method to identify protein sequences that fold into a known three-dimensional structure. Science 1991;253:164–170.PubMedCrossRefGoogle Scholar
  30. 30.
    Friedman AM, Fischmann TO, Steitz TA. Crystal structure of lac repressor core tetramer and its implications for DNA looping. Science 1995;268:1721–1727.PubMedCrossRefGoogle Scholar
  31. 31.
    Schumacher MA, Choi KY, Zalkin H, Brennan RG. Crystal structure of lacl member, PurR, bound to DNA: minor groove binding by alpha helices. Science 1994;266:763–770.PubMedCrossRefGoogle Scholar
  32. 32.
    Nohno T, Saito T, Hong JS. Cloning and complete nucleotide sequence of the Escherichia coli glutamine permease operon (glnHPQ). Mol. Gen. Genet. 1986;205:260–269.PubMedCrossRefGoogle Scholar
  33. 33.
    Kaneko T, Sato S, Kotani H, et al. Sequence analysis of the genome of the unicellular cyanobacterium Synechocystis sp. strain PCC6803. II. Sequence determination of the entire genome and assignment of potential protein-coding regions. DNA Res. 1996;3:109–136.PubMedCrossRefGoogle Scholar
  34. 34.
    Graul RC, Sadée W. Sequence alignments of the H+-dependent oligopeptide transporter family PTR: inferences on structure and function of the intestinal PET1 transporter. Pharm. Res. 1997;14:388–400.PubMedCrossRefGoogle Scholar
  35. 35.
    Nayak A, Zastrow DJ, Lickteig R, Zahniser NR, Browning MD. Maintenance of late-phase LTP is accompanied by PKA-dependent increase in AMPA receptor synthesis. Nature 1998;394:680–683.PubMedCrossRefGoogle Scholar
  36. 36.
    Armstrong N, Sun Y, Chen GQ, Gouaux E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 1998;395:913–917.PubMedCrossRefGoogle Scholar
  37. 37.
    Masu M, Tanabe Y, Tsuchida K, Shigemoto R, Nakanishi S. Sequence and expression of a metabotropic glutamate receptor. Nature 1991;349:760–765.PubMedCrossRefGoogle Scholar
  38. 38.
    Houamed KM, Kuijper JL, Gilbert TL, et al. Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science 1991;252:1318–1321.PubMedCrossRefGoogle Scholar
  39. 39.
    Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998;281:1349–1352.PubMedCrossRefGoogle Scholar
  40. 40.
    Cockcroft VB, Ortells MO, Thomas P, Lunt GG. Homologies and disparities of glutamate receptors: a critical analysis. Neurochem. Int. 1993;23:583–594.PubMedCrossRefGoogle Scholar
  41. 41.
    Kaupmann K, Huggel K, Heid J, et al. Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature 1997;386:239–246.PubMedCrossRefGoogle Scholar
  42. 42.
    Aprison MH, Galvez-Ruano E, Lipkowitz KB. The nicotinic cholinergic receptor: a theoretical model. J. Neurosci. Res. 1996;46:226–230.PubMedCrossRefGoogle Scholar
  43. 43.
    Smith GB, Olsen RW. Functional domains of GABAA receptors. Trends Pharmacol. Sci. 1995;16:162–168.PubMedCrossRefGoogle Scholar
  44. 44.
    Brown EM, Vassilev PM, Hebert SC. Calcium ions as extracellular messengers. Cell 1995;83:679–682.PubMedCrossRefGoogle Scholar
  45. 45.
    Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine REFthyroid. Nature 1993;366:575–580.PubMedCrossRefGoogle Scholar
  46. 46.
    Garrett JE, Capuano IV, Hammerland LG, et al. Molecular cloning and functional expression of human REFthyroid calcium receptor cDNAs. J. Biol. Chem. 1995;270:12919–12925.PubMedCrossRefGoogle Scholar
  47. 47.
    Vyas NK, Vyas MN, Quiocho FA. A novel calcium binding site in the galactose-binding protein of bacterial transport and chemotaxis. Nature 1987;327:635–638.PubMedCrossRefGoogle Scholar
  48. 48.
    Kubo Y, Miyashita T, Murata Y. Structural basis for a Ca2+-sensing function of the metabotropic glutamate receptors. Science. 1998;279:1722–1725.PubMedCrossRefGoogle Scholar
  49. 49.
    Baron J, Winer KK, Yanovski JA, et al. Mutations in the Ca2+-sensing receptor gene cause autosomal dominant and sporadic hypoREFthyroidism. Hum. Mol. Genet. 1996;5:601–606.PubMedCrossRefGoogle Scholar
  50. 50.
    Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperREFthyroidism. Cell 1993;75:1297–1303.PubMedCrossRefGoogle Scholar
  51. 51.
    Pearce SH, Trump D, Wooding C, et al. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperREFthyroidism. J. Clin. Invest. 1995;96:2683–2692.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Herrada G, Dulac C. A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 1997;90:763–773.PubMedCrossRefGoogle Scholar
  53. 53.
    Dulac C, Axel R. A novel family of genes encoding putative pheromone receptors in mammals. Cell 1995;83:195–206.PubMedCrossRefGoogle Scholar
  54. 54.
    Nakao K, Itoh H, Saito Y, Mukoyama M, Ogawa Y. The natriuretic peptide family. Cur. Opin. Nephrol. Hypertension 1996;5:4–11.CrossRefGoogle Scholar
  55. 55.
    Romano C, Yang WL, O’Malley KL. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem. 1996;271:28612–28616.PubMedCrossRefGoogle Scholar
  56. 56.
    Ward DT, Brown EM, Harris HW. Disulfide bonds in the extracellular calcium-polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro. J. Biol. Chem. 1998;273:14476–14483.PubMedCrossRefGoogle Scholar
  57. 57.
    Jones KA, Borowsky B, Tamm JA, et al. GABABreceptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature 1998;396:674–679.PubMedCrossRefGoogle Scholar
  58. 58.
    White JH, Wise A, Main MJ, et al. Heterodimerization is required for the formation of a functional GABAB receptor. Nature 1998;396:679–682.PubMedCrossRefGoogle Scholar
  59. 59.
    Kaupmann K, Malitschek B, Schuler V, et al. GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature 1998;396:683–687.PubMedCrossRefGoogle Scholar
  60. 60.
    Nakao K, Ogawa Y, Suga S, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. II: Natriuretic peptide receptors. J. Hypertens. 1992;10:1111–1114.PubMedCrossRefGoogle Scholar
  61. 61.
    Nakao K, Ogawa Y, Suga S, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. I: Natriuretic peptides. J. Hypertens. 1992;10:907–912.PubMedGoogle Scholar
  62. 62.
    Chang MS, Lowe DG, Lewis M, Hellmiss R, Chen E. Goeddel DV. Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases. Nature 1989;341:68–72.PubMedCrossRefGoogle Scholar
  63. 63.
    Schulz S, Singh S, Bellet RA, et al. The primary structure of a plasma membrane guanylate cyclase demonstrates diversity within this new receptor family. Cell 1989;58:1155–1162.PubMedCrossRefGoogle Scholar
  64. 64.
    Lowe DG, Chang MS, Hellmiss R, et al. Human atrial natriuretic peptide receptor defines a new REF digm for second messenger signal transduction. Embo J. 1989;8:1377–1384.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Fuller F, Porter JG, Arfsten AE, et al. Atrial natriuretic peptide clearance receptor. Complete sequence and functional expression of cDNA clones. J. Biol. Chem. 1988;263:9395–9401.PubMedGoogle Scholar
  66. 66.
    Lowe DG, Camerato TR, Goeddel DV. cDNA sequence of the human atrial natriuretic peptide clearance receptor. Nucleic Acids Res. 1990;18:3412.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Chinkers M, Garbers DL. The protein kinase domain of the ANP receptor is required for signaling. Science 1989;245:1392–1394.PubMedCrossRefGoogle Scholar
  68. 68.
    Kishimoto I, Yoshimasa T, Suga S, et al. Natriuretic peptide clearance receptor is transcriptionally down-regulated by b2-adrenergic stimulation in vascular smooth muscle cells. J. Biol. Chem. 1994;269:28300–28308.PubMedGoogle Scholar
  69. 69.
    Kishimoto I, Nakao K, Suga S, et al. Downregulation of C-receptor by natriuretic peptides via ANP-B receptor in vascular smooth muscle cells. Amer. J. Physiol. 1993;265:H1373–1379.PubMedGoogle Scholar
  70. 70.
    Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and Gtype natriuretic peptide. Endocrinology 1992;130:229–239.PubMedGoogle Scholar
  71. 71.
    Koller KJ, Lowe DG, Bennett GL, et al. Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 1991;252:120–123.PubMedCrossRefGoogle Scholar
  72. 72.
    Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994;22:4673–4680.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Gardner J, SeqVu. The Garvan Institute of Medical Research, 384 Victoria Rd., Darlinghurst NSW 2010, Sydney Australia, Sydney. Australia, 1998.Google Scholar
  74. 74.
    Felsenstein J. Inferring phylogenies from protein sequences by parsimony, distance, and likelihood methods. Methods Enzymol. 1996;266:418–427.PubMedCrossRefGoogle Scholar
  75. 75.
    Page RD. TreeView: An application to display phylogenetic trees on personal computers. Comput. Appl. Biosci. 1996;12:357–358.PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 1999

Authors and Affiliations

  • Christian B. Felder
    • 1
  • Richard C. Graul
    • 2
  • Alan Y. Lee
    • 2
  • Hans-Peter Merkle
  • Wolfgang Sadee
    • 2
  1. 1.Department of PharmacyETH ZurichZurichSwitzerland
  2. 2.Department of Biopharmaceutical Sciences and Pharmaceutical ChemistryUniversity of CaliforniaSan Francisco

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