Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue

EMBO Reports

Volumn 13, Issue 9, 2012, Pages 861-866

  Wang, Hui ^a   Gouaux, Eric ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

neurotransmitter uptake; sodium coupled transporter; X ray crystallography

Indexed keywords

CLOMIPRAMINE; LEUT PROTEIN; MUTANT PROTEIN; NEUROTRANSMITTER; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; BINDING SITE; EXPERIMENTAL STUDY; HIGH AFFINITY SUBSTRATE BINDING SITE; LIGAND BINDING; NEUROTRANSMITTER UPTAKE; PRIORITY JOURNAL; PROTEIN STRUCTURE; X RAY CRYSTALLOGRAPHY;

BINDING SITES; CRYSTALLOGRAPHY, X-RAY; HUMANS; MOLECULAR DOCKING SIMULATION; MUTATION; PLASMA MEMBRANE NEUROTRANSMITTER TRANSPORT PROTEINS; SODIUM;

EID: 84865730840     PISSN: 1469221X     EISSN: 14693178     Source Type: Journal    
DOI: 10.1038/embor.2012.110     Document Type: Article

References (33)

1. Hahn MK, Blakely RD (2002) Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J 2: 217-235
2. Richerson G, Wu Y (2004) Role of the GABA transporter in epilepsy. Adv Exp Med Biol 548: 76-91
3. White K, Walline C, Barker E (2005) Serotonin transporters: implications for antidepressant drug development. AAPS J 7: 421-433
4. Iversen L (2006) Neurotransmitter transporters and their impact on the development of psychopharmacology. Br J Pharmacol 147: 82-88
5. Amara SG, Sonders MS (1998) Neurotransmitter transporters as molecular targets for addictive drugs. Drug Alcohol Depend 51: 87-96
6. 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
7. Boudker O, Verdon G (2010) Structural perspectives on secondary active transporters. Trends Pharmacol Sci 31: 418-426
8. Forrest LR, Kramer R, Ziegler C (2011) The structural basis of secondary active transport mechanisms. Biochim Biophys. Acta (BBA)-Bioenergetics 1807: 167-188
9. Kanner BI, Zomot E (2008) Sodium-coupled neurotransmitter transporters. Chem Rev 108: 1654-1668
10. Krishnamurthy H, Piscitelli CL, Gouaux E (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459: 347-355
11. Kristensen AS, Andersen J, Jorgensen TN, Sorensen L, Eriksen J, Loland CJ, Stromgaard K, Gether U (2011) SLC6 neurotransmitter transporters: structure, function, and regulation. Pharmacol Rev 63: 585-640
12. Rudnick G (2011) Cytoplasmic permeation pathway of neurotransmitter transporters. Biochemistry 50: 7462-7475
13. Reyes N, Tavoulari S (2011) To be, or not to be two sites: that is the question about LeuT substrate binding. J Gen Physiol 138: 467-471
14. Singh SK, Piscitelli CL, Yamashita A, Gouaux E (2008) A competitive inhibitor traps LeuT in an open-to-out conformation. Science 322: 1655-1661
15. Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448: 952-956
16. Wang H, Elferich J, Gouaux E (2012) Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context. Nat Struct Mol Biol 19: 212-219
17. Piscitelli CL, Krishnamurthy H, Gouaux E (2010) Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site. Nature 468: 1129-1132
18. Quick M, Shi L, Zehnpfennig B, Weinstein H, Javitch JA (2012) Experimental conditions can obscure the second high-affinity site in LeuT. Nat Struct Mol Biol 19: 207-211
19. Quick M, Winther A-ML, Shi L, Nissen P, Weinstein H, Javitch JA (2009) Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation. Proc Natl Acad Sci 106: 5563-5568
20. 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
21. Zhao Y, Terry DS, Shi L, Quick M, Weinstein H, Blanchard SC, Javitch JA (2011) Substrate-modulated gating dynamics in a Na +coupled neurotransmitter transporter homologue. Nature 474: 109-113
22. Zhao Y, Terry D, Shi L, Weinstein H, Blanchard SC, Javitch JA (2010) Single-molecule dynamics of gating in a neurotransmitter transporter homologue. Nature 465: 188-193
23. Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith MEA, Wang DN (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317: 1390-1393
24. Chae PS et al Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins (2010) Nat Meth 7: 1003-1008
25. Quick M, Javitch JA (2007) Monitoring the function of membrane transport proteins in detergent-solubilized form. Proc Natl Acad Sci 104: 3603-3608
26. Kawate T, Gouaux E (2006) Fluorescence-detection size-exclusion chromatography for precrystallization screening of integral membrane proteins. Structure 14: 673-681
27. Faham S, Bowie JU (2002) Bicelle crystallization: a new method for crystallizing membrane proteins yields a monomeric bacteriorhodopsin structure. J Mol Biol 316: 1-6
28. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected inoscillation mode. Methods Enzymol 276: 307-326
29. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658-674
30. Collaborative (1994) The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50: 760-763
31. Adams PD et al (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66: 213-221
32. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126-2132
33. Chen VB, Arendall WB III, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66: 12-21