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.
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References
Landry Y, Gies JP (2008) Drugs and their molecular targets: An updated overview. Fundam Clin Pharmacol 22:1–18
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
Saier MH, Jr. (2000) A functional-phylogenetic classification system for transmembrane solute transporters. Microbiol Mol Biol Rev 64:354–411
Rang HP, Dale MM, Ritter JM, Morre PK (2003) Pharmacology. 5th edn. Churchill Livingstone, ISBN-10 / ASIN: 0443071454
Caffrey M (2003) Membrane protein crystallization. J Struct Biol 142:108–132
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
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
Frishman D, Mewes HW (1997) Protein structural classes in five complete genomes. Nat Struct Biol 4:626–628
Wallin E, von Heijne G (1998) Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci 7:1029–1038
Bradley P, Misura KM, Baker D (2005) Toward high-resolution de novo structure prediction for small proteins. Science 309:1868–1871
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
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
Eddy SR (1998) Profile hidden markov models. Bioinformatics 14:755–763
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
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
Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug abc transporter. Nature
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
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
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.
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
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
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
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
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
Vriend G (1990) What if: A molecular modeling and drug design program. J Mol Graph 8:52–56, 29
Levitt M (1992) Accurate modeling of protein conformation by automatic segment matching. J Mol Biol 226:507–533
Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815
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
Hooft RW, Vriend G, Sander C, Abola EE (1996) Errors in protein structures. Nature 381:272
Kryshtafovych A, Venclovas C, Fidelis K, Moult J (2005) Progress over the first decade of casp experiments. Proteins 61 Suppl 7:225–236
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
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
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
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
Higgins CF, Linton KJ (2001) Structural biology. The xyz of abc transporters. Science 293:1782–1784
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
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
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
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
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
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
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
Loo TW, Bartlett MC, Clarke DM (2006) Transmembrane segment 7 of human p-glycoprotein forms part of the drug-binding pocket. Biochem J
Loo TW, Clarke DM (2002) Location of the rhodamine-binding site in the human multidrug resistance p-glycoprotein. J Biol Chem 277:44332–44338
Loo TW, Clarke DM (2005) Recent progress in understanding the mechanism of p-glycoprotein-mediated drug efflux. J Membr Biol 206:173–185
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
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
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
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
Borst P, de Wolf C, van de Wetering K (2007) Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453:661–673
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
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
Ravna AW, Sylte I, Dahl SG (2009) Structure and localisation of drug binding sites on neurotransmitter transporters. J Mol Model
Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956
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
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
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
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
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.
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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
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DOI: https://doi.org/10.1007/978-1-61779-588-6_12
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