A steered molecular dynamics study of binding and translocation processes in the GABA transporter

PLoS ONE

Volumn 7, Issue 6, 2012, Pages

  Skovstrup, Søren ^a,b   David, Laurent ^b   Taboureau, Olivier ^c   Jørgensen, Flemming Steen ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b H LUNDBECK A S   (Denmark)

^c TECHNICAL UNIVERSITY OF DENMARK   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID CARRIER; LYSINE; TIAGABINE;

ARTICLE; BINDING SITE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; DRUG INHIBITION; DRUG MECHANISM; DRUG PROTEIN BINDING; LIGAND BINDING; MOLECULAR DYNAMICS; MOLECULAR MECHANICS; PROTEIN INTERACTION; PROTEIN TRANSPORT;

ANTICONVULSANTS; BINDING SITES; CYTOPLASM; GABA PLASMA MEMBRANE TRANSPORT PROTEINS; GAMMA-AMINOBUTYRIC ACID; HUMANS; KINETICS; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR DYNAMICS SIMULATION; NIPECOTIC ACIDS; PROTEIN BINDING; PROTEIN CONFORMATION;

EID: 84862686732     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0039360     Document Type: Article

References (59)

1. Braestrup C, Nielsen EB, Sonnewald U, Knutsen LJ, Andersen KE, et al. (1990) (R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid binds with high affinity to the brain gamma-aminobutyric acid uptake carrier. J Neurochem 54: 639-647.
2. 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.
3. Celik L, Schiott B, Tajkhorshid E, (2008) Substrate binding and formation of an occluded state in the leucine transporter. Biophys J 94: 1600-1612.
4. 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.
5. Piscitelli CL, Krishnamurthy H, Gouaux E, (2010) Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature 468: 1129-1132.
6. Singh SK, Yamashita A, Gouaux E, (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448: 952-956.
7. 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.
8. Singh SK, Piscitelli CL, Yamashita A, Gouaux E, (2008) A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322: 1655-1661.
9. Quick M, Winther AM, 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 U S A 106: 5563-5568.
10. Zhou Z, Zhen J, Karpowich NK, Law CJ, Reith ME, et al. (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat Struct Mol Biol 16: 652-657.
11. Celik L, Schiøtt B, Tajkhorshid E, (2008) Substrate binding and formation of an occluded state in the leucine transporter. Biophys J 94: 1600-1612.
12. Forrest LR, Zhang YW, Jacobs MT, Gesmonde J, Xie L, et al. (2008) Mechanism for alternating access in neurotransmitter transporters. Proc Natl Acad Sci U S A 105: 10338-10343.
13. 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.
14. 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.
15. Schousboe A, Sarup A, Larsson OM, White HS, (2004) GABA transporters as drug targets for modulation of GABAergic activity. Biochem Pharmacol 68: 1557-1563.
16. Clausen RP, Frolund B, Larsson OM, Schousboe A, Krogsgaard-Larsen P, et al. (2006) A novel selective gamma-aminobutyric acid transport inhibitor demonstrates a functional role for GABA transporter subtype GAT2/BGT-1 in the CNS. Neurochem Int 48: 637-642.
17. Madsen KK, Clausen RP, Larsson OM, Krogsgaard-Larsen P, Schousboe A, et al. (2009) Synaptic and extrasynaptic GABA transporters as targets for anti-epileptic drugs. J Neurochem 109: 139-144.
18. Madsen KK, White HS, Schousboe A, (2010) Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs. Pharmacol Ther 125: 394-401.
19. Skovstrup S, Taboureau O, Braüner-Osborne H, Jørgensen FS, (2010) Homology modelling of the GABA transporter and analysis of tiagabine binding. ChemMedChem 5: 986-1000.
20. Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, et al. (2006) Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem 281: 2012-2023.
21. 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 recognition of citalopram and tricyclic antidepressants. J Biol Chem 284: 10276-10284.
22. Clausen RP, Madsen K, Larsson OM, Frolund B, Krogsgaard-Larsen P, et al. (2006) Structure-activity relationship and pharmacology of gamma-aminobutyric acid (GABA) transport inhibitors. Adv Pharmacol 54: 265-284.
23. Grubmuller H, Heymann B, Tavan P, (1996) Ligand binding: molecular mechanics calculation of the streptavidin-biotin rupture force. Science 271: 997-999.
24. Sotomayor M, Schulten K, (2007) Single-molecule experiments in vitro and in silico. Science 316: 1144-1148.
25. Genchev GZ, Kallberg M, Gursoy G, Mittal A, Dubey L, et al. (2009) Mechanical signaling on the single protein level studied using steered molecular dynamics. Cell Biochem Biophys 55: 141-152.
26. Amaro RE, Sethi A, Myers RS, Davisson VJ, Luthey-Schulten ZA, (2007) A network of conserved interactions regulates the allosteric signal in a glutamine amidotransferase. Biochemistry 46: 2156-2173.
27. Jensen MO, Yin Y, Tajkhorshid E, Schulten K, (2007) Sugar transport across lactose permease probed by steered molecular dynamics. Biophys J 93: 92-102.
28. Mai BK, Viet MH, Li MS, (2010) Top Leads for Swine Influenza A/H1N1 Virus Revealed by Steered Molecular Dynamics Approach. J Chem Inf Model.
29. MacAulay N, Meinild AK, Zeuthen T, Gether U, (2003) Residues in the extracellular loop 4 are critical for maintaining the conformational equilibrium of the gamma-aminobutyric acid transporter-1. J Biol Chem 278: 28771-28777.
30. Meinild AK, Loo DD, Skovstrup S, Gether U, MacAulay N, (2009) Elucidating conformational changes in the gamma-aminobutyric acid transporter-1. J Biol Chem 284: 16226-16235.
31. Tamura S, Nelson H, Tamura A, Nelson N, (1995) Short external loops as potential substrate binding site of gamma-aminobutyric acid transporters. J Biol Chem 270: 28712-28715.
32. Zomot E, Kanner BI, (2003) The interaction of the gamma-aminobutyric acid transporter GAT-1 with the neurotransmitter is selectively impaired by sulfhydryl modification of a conformationally sensitive cysteine residue engineered into extracellular loop IV. J Biol Chem 278: 42950-42958.
33. 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.
34. Gether U, Andersen PH, Larsson OM, Schousboe A, (2006) Neurotransmitter transporters: molecular function of important drug targets. Trends Pharmacol Sci 27: 375-383.
35. Kanner BI, Zomot E, (2008) Sodium-coupled neurotransmitter transporters. Chem Rev 108: 1654-1668.
36. Cherubino F, Miszner A, Renna MD, Sangaletti R, Giovannardi S, et al. (2009) GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction. Cell Mol Life Sci 66: 3797-3808.
37. Forlani G, Bossi E, Ghirardelli R, Giovannardi S, Binda F, et al. (2001) Mutation K448E in the external loop 5 of rat GABA transporter rGAT1 induces pH sensitivity and alters substrate interactions. J Physiol 536: 479-494.
38. Rosenberg A, Kanner BI, (2008) The substrates of the gamma-aminobutyric acid transporter GAT-1 induce structural rearrangements around the interface of transmembrane domains 1 and 6. J Biol Chem 283: 14376-14383.
39. Keshet GI, Bendahan A, Su H, Mager S, Lester HA, et al. (1995) Glutamate-101 is critical for the function of the sodium and chloride-coupled GABA transporter GAT-1. FEBS Lett 371: 39-42.
40. Bismuth Y, Kavanaugh MP, Kanner BI, (1997) Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition. J Biol Chem 272: 16096-16102.
41. Zhou Y, Bennett ER, Kanner BI, (2004) The aqueous accessibility in the external half of transmembrane domain I of the GABA transporter GAT-1 Is modulated by its ligands. J Biol Chem 279: 13800-13808.
42. Pantanowitz S, Bendahan A, Kanner BI, (1993) Only one of the charged amino acids located in the transmembrane alpha-helices of the gamma-aminobutyric acid transporter (subtype A) is essential for its activity. J Biol Chem 268: 3222-3225.
43. Kanner BI, (2003) Transmembrane domain I of the gamma-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J Biol Chem 278: 3705-3712.
44. Kleinberger-Doron N, Kanner BI, (1994) Identification of tryptophan residues critical for the function and targeting of the gamma-aminobutyric acid transporter (subtype A). J Biol Chem 269: 3063-3067.
45. Mager S, Kleinberger-Doron N, Keshet GI, Davidson N, Kanner BI, et al. (1996) Ion binding and permeation at the GABA transporter GAT1. J Neurosci 16: 5405-5414.
46. Yu N, Cao Y, Mager S, Lester HA, (1998) Topological localization of cysteine 74 in the GABA transporter, GAT1, and its importance in ion binding and permeation. FEBS Lett 426: 174-178.
47. Melamed N, Kanner BI, (2004) Transmembrane domains I and II of the gamma-aminobutyric acid transporter GAT-4 contain molecular determinants of substrate specificity. Mol Pharmacol 65: 1452-1461.
48. Dodd JR, Christie DL, (2007) Selective amino acid substitutions convert the creatine transporter to a gamma-aminobutyric acid transporter. J Biol Chem 282: 15528-15533.
49. Bennett ER, Su H, Kanner BI, (2000) Mutation of arginine 44 of GAT-1, a (Na(+) + Cl(-))-coupled gamma-aminobutyric acid transporter from rat brain, impairs net flux but not exchange. J Biol Chem 275: 34106-34113.
50. Bendahan A, Kanner BI, (1993) Identification of domains of a cloned rat brain GABA transporter which are not required for its functional expression. FEBS Lett 318: 41-44.
51. Deken SL, Beckman ML, Boos L, Quick MW, (2000) Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A. Nat Neurosci 3: 998-1003.
52. Hansra N, Arya S, Quick MW, (2004) Intracellular domains of a rat brain GABA transporter that govern transport. J Neurosci 24: 4082-4087.
53. Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, et al. (2006) Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters. Proceedings of the ACM/IEEE Conference on Super-computing (SC06).
54. D. E. Shaw Research, (2009) Desmond Molecular Dynamics System, version 2.2, Maestro-Desmond Interoperability Tools, version 2.2, Schrödinger. New York, NY, USA.
55. Schrödinger LLC, (2009) Maestro, Version 9.0. New York, NY, USA.
56. Jarzynski C, (1997) Equilibrium free-energy differences from nonequilibrium measurements: A master-equation approach. Physical Review E 56: 5018-5035.
57. Jarzynski C, (1997) Nonequilibrium equality for free energy differences. Physical Review Letters 78: 2690-2693.
58. Humphrey W, Dalke A, Schulten K, (1996) VMD- Visual Molecular Dynamics. Journal of Molecular Graphics 14: 33-38.
59. Schrodinger LLC, (2010) The PyMOL Molecular Graphics System, Version 1.3r1.