Unbiased simulations reveal the inward-facing conformation of the human serotonin transporter and Na+ ion release

PLoS Computational Biology

Volumn 7, Issue 10, 2011, Pages

  Koldsø, Heidi ^a   Noer, Pernille ^b   Grouleff, Julie ^a   Autzen, Henriette Elisabeth ^a   Sinning, Steffen ^b   Schiøtt, Birgit ^a  

^a AARHUS UNIVERSITY   (Denmark)

^b AARHUS UNIVERSITY HOSPITAL   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

CONTROLLED DRUG DELIVERY; CRYSTAL STRUCTURE; CYTOLOGY; DIMERS; FACINGS; ION EXCHANGE; IONS; MOLECULAR DYNAMICS; TARGETED DRUG DELIVERY;

CRYSTALS STRUCTURES; DRUG OF ABUSE; HOMOLOGY MODELING; ION RELEASE; MECHANISTICS; NA+ IONS; NEUROLOGICAL PROCESS; SEROTONIN TRANSPORTERS; STRUCTURAL KNOWLEDGE; TRANSPORT MECHANISM;

SUBSTRATES;

ASPARAGINE; ASPARTIC ACID; LIGAND; MEMBRANE PROTEIN; SEROTONIN TRANSPORTER; SODIUM ION; TRANSMEMBRANE HELIX 1 PROTEIN; TRANSMEMBRANE HELIX 6 PROTEIN; UNCLASSIFIED DRUG; SLC6A4 PROTEIN, HUMAN; SODIUM; WATER;

ARTICLE; BINDING AFFINITY; BINDING SITE; CHANNEL GATING; COMPUTER MODEL; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CYTOPLASM; EXTRACELLULAR MATRIX; HUMAN; HUMAN CELL; INTRACELLULAR TRANSPORT; MEMBRANE CHANNEL; MOLECULAR DYNAMICS; MOLECULAR MODEL; PREDICTION; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DETERMINATION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN TRANSPORT; SODIUM TRANSPORT; SOLVATION; STRUCTURAL HOMOLOGY; BIOLOGICAL MODEL; CHEMISTRY; GENETICS; METABOLISM; MUTATION; SITE DIRECTED MUTAGENESIS;

BINDING SITES; CYTOPLASM; HUMANS; MODELS, BIOLOGICAL; MOLECULAR DYNAMICS SIMULATION; MUTAGENESIS, SITE-DIRECTED; MUTATION; PROTEIN BINDING; PROTEIN CONFORMATION; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS; SODIUM; WATER;

EID: 80055067598     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1002246     Document Type: Article

References (56)

1. Rudnick G, (2002) Mechanisms of biogenic amine neurotransmitter transporters. In: Reith MEA, editors. Neurotransmitter Transporters: Structure, Function, and Regulation Totowa, NJ Humana Press pp. 25-52.
2. Torres GE, Gainetdinov RR, Caron MG, (2003) Plasma membrane monoamine transporters: Structure, regulation and function. Nat Rev Neurosci 4: 13-25.
3. Koldsø H, Severinsen K, Tran TT, Celik L, Jensen HH, et al. (2010) The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations. J Am Chem Soc 132: 1311-1322.
4. Sinning S, Musgaard M, Jensen M, Severinsen K, Celik L, et al. (2010) Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter. J Biol Chem 285: 8363-8374.
5. Celik L, Sinning S, Severinsen K, Hansen C, Møller M, et al. (2008) Binding of serotonin to the human serotonin transporter. molecular modeling and experimental validation. J Am Chem Soc 130: 3853-3865.
6. Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, et al. (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11: 780-789.
7. Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, et al. (2009) Location of the antidepressant binding site in the serotonin transporter: Importance of ser-438 in the recognition of citalopram and tricyclic antidepressants. J Biol Chem 284: 10276-10284.
8. 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.
9. Singh SK, Piscitelli CL, Yamashita A, Gouaux E, (2008) A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322: 1655-1661.
10. Singh SK, Yamashita A, Gouaux E, (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448: 952-956.
11. Quick M, Winther AL, Shi L, Nissen P, Weinstein H, et al. (2009) Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation. Proc Natl Acad Sci USA 106: 5563-5568.
12. Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, et al. (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317: 1390-1393.
13. Zhou Z, Zhen J, Karpowich NK, Law CJ, Reith MEA, et al. (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat Struct Mol Biol 16: 652-658.
14. Kroncke BM, Horanyi PS, Columbus L, (2010) Structural origins of nitroxide side chain dynamics on membrane protein α-helical sites. Biochemistry 49: 10045-10060.
15. Weyand S, Shimamura T, Beckstein O, Sansom MSP, Iwata S, et al. (2010) The alternating access mechanism of transport as observed in the sodium-hydantoin transporter Mhp1. J Synchrotron Rad 18: 20-23.
16. Shimamura T, Weyand S, Beckstein O, Rutherford NG, Hadden JM, et al. (2010) Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. Science 328: 470-473.
17. Fang Y, Jayaram H, Shane T, Kolmakova-Partensky L, Wu F, et al. (2009) Structure of a prokaryotic virtual proton pump at 3.2 Å resolution. Nature 460: 1040-1043.
18. Shaffer PL, Goehring A, Shankaranarayanan A, Gouaux E, (2009) Structure and mechanism of a na+-independent amino acid transporter. Science 325: 1010-1014.
19. 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: 233-236.
20. 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: 47-52.
21. Faham S, Watanabe A, Besserer GM, Cascio D, Specht A, et al. (2008) The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/Sugar symport. Science 321: 810-814.
22. Tang L, Bai L, Wang W, Jiang T, (2010) Crystal structure of the carnitine transporter and insights into the antiport mechanism. Nat Struct Mol Biol 17: 492-496.
23. Kowalczyk L, Ratera M, Paladino A, Bartoccioni P, Errasti-Murugarren E, et al. (2011) Molecular basis of substrate-induced permeation by an amino acid antiporter. Proc Natl Acad Sci USA 108: 3935-3940.
24. Forrest LR, Zhang Y, Jacobs MT, Gesmonde J, Xie L, et al. (2008) Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci USA 105: 10338-10343.
25. Jardetzky O, (1966) Simple allosteric model for membrane pumps. Nature 211: 969-970.
26. 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: 667-677.
27. Celik L, Schiøtt B, Tajkhorshid E, (2008) Substrate binding and formation of an occluded state in the leucine transporter. Biophys J 94: 1600-1612.
28. Shan J, Javitch JA, Shi L, Weinstein H, (2011) The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter. PLoS ONE 6: e16350.
29. Forrest LR, Rudnick G, (2009) The rocking bundle: A mechanism for ion-coupled solute flux by symmetrical transporters. Physiology 24: 377-386.
30. Radestock S, Forrest LR, (2011) The alternating-access mechanism of MFS transporters arises from inverted-topology repeats. J Mol Biol 407: 698-715.
31. Piscitelli CL, Krishnamurthy H, Gouaux E, (2010) Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature 468: 1129-1132.
32. Tavoulari S, Forrest LR, Rudnick G, (2009) Fluoxetine (prozac) binding to serotonin transporter is modulated by chloride and conformational changes. J Neurosci 29: 9635-9643.
33. Jacobs MT, Zhang Y, Campbell SD, Rudnick G, (2007) Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. J Biol Chem 282: 29441-29447.
34. Zhang Y, Rudnick G, (2006) The cytoplasmic susbtrate permeation pathway of serotonin transporter. J Biol Chem 281: 36213-36220.
35. Zhao Y, Terry D, Shi L, Weinstein H, Blanchard SC, et al. (2010) Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature 465: 188-193.
36. Claxton DP, Quick M, Shi L, de Carvalho FD, Weinstein H, et al. (2010) Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:Sodium symporters. Nat Struct Mol Biol 17: 822-829.
37. Kilic F, Rudnick G, (2000) Oligomerization of serotonin transporter and its functional consequences. Proc Natl Acad Sci U S A 97: 3106-3111.
38. Fjorback AW, Pla P, Müller HK, Wiborg O, Saudou F, et al. (2009) Serotonin transporter oligomerization documented in RN46A cells and neurons by sensitized acceptor emission FRET and fluorescence lifetime imaging microscopy. Biochem Biophys Res Commun 380: 724-728.
39. Sitte HH, Farhan H, Javitch JA, (2004) Sodium-dependent neurotransmitter transporters: Oligomerization as a determinant of transporter function and trafficking. Mol Interv 4: 38-47.
40. Aittoniemi J, de Wet H, Ashcroft FM, Sansom MSP, (2010) Asymmetric switching in a homodimeric ABC transporter: A simulation study. PLoS Comput Biol 6: e1000762.
41. Kniazeff J, Shi L, Loland CJ, Javitch JA, Weinstein H, et al. (2008) An intracellular interaction network regulates conformational transitions in the dopamine transporter. J Biol Chem 283: 17691-17701.
42. Shaikh SA, Tajkhorshid E, (2010) Modeling and dynamics of the inward-facing state of a Na+/Cl- dependent neurotransmitter transporter homologue. PLoS Comput Biol 6: e1000905.
43. Zhao C, Noskov SY, (2011) The role of local hydration and hydrogen-bonding dynamics in ion and solute release from ion-coupled secondary transporters. Biochemistry 50: 1848-1856.
44. Smart OS, Goodfellow JM, Wallace BA, (1993) The pore dimensions of gramicidin A. Biophys J 65: 2455-2460.
45. Smart OS, Neduvelil JG, Wang X, Wallace BA, Sansom MSP, (1996) HOLE: A program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph 14: 354-360.
46. Kilic F, Murphy DL, Rudnick G, (2003) A human serotonin transporter mutation causes constitutive activation of transport activity. Mol Pharmacol 64: 440-446.
47. Apparsundaram S, Stockdale DJ, Henningsen RA, Milla ME, Martin RS, (2008) Antidepressants targeting the serotonin reuptake transporter act via a competitive mechanism. J Pharmacol Exp Ther 327: 982-990.
48. Hyttel J, (1978) Effect of a specific 5-HT uptake inhibitor, citalopram (lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro. Psychopharmacology 60: 13-18.
49. Sherman W, Day T, Jacobson MP, Friesner RA, Farid R, (2006) Novel procedure for modeling Ligand/Receptor induced fit effects. J Med Chem 49: 534-553.
50. Schrödinger Suite (2008) Induced Fit Docking protocol, Glide version 5.0, Prime version 1.7 New York Schrödinger, LLC.
51. Humphrey W, Dalke A, Schulten K, (1996) VMD: Visual molecular dynamics. J Mol Graph 14: 33-38.
52. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML, (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79: 926-935.
53. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, et al. (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26: 1781-1802.
54. MacKerell ADJ, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, et al. (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102: 3586-3616.
55. MacKerell ADJ, Feig M, Brooks CL III, (2004) Extending the treatment of backbone energetics in protein force fields: Limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem 25: 1400-1415.
56. MacKerell ADJ, Feig M, Brooks CL III, (2004) Improved treatment of the protein backbone in empirical force fields. J Am Chem Soc 126: 698-699.