Ligand Discovery for the Alanine-Serine-Cysteine Transporter (ASCT2, SLC1A5) from Homology Modeling and Virtual Screening

PLoS Computational Biology

Volumn 11, Issue 10, 2015, Pages

  Colas, Claire ^a   Grewer, Christof ^b   Otte, Nicholas James ^c,d   Gameiro, Armanda ^b   Albers, Thomas ^b   Singh, Kurnvir ^b   Shere, Helen ^a   Bonomi, Massimiliano ^e   Holst, Jeff ^c,d   Schlessinger, Avner ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b BINGHAMTON UNIVERSITY   (United States)

^c Origins of Cancer Laboratory Centenary Program   (Australia)

^d UNIVERSITY OF SYDNEY   (Australia)

^e UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BINDING SITES; BIOLOGICAL MEMBRANES; CARBOXYLATION; CELL CULTURE; DERMATOLOGY; DIAGNOSIS; DISEASES; ELECTROPHYSIOLOGY; LIGANDS; ONCOLOGY; PROTEINS;

AMINO-ACIDS; DRUG TARGETS; EXPERIMENTAL TESTING; HOMOEOSTASIS; HOMOLOGY MODELING; INTRACELLULAR CONCENTRATION; MEMBRANE PROTEINS; MODEL SCREENING; PERIPHERAL TISSUE; VIRTUAL SCREENING;

AMINO ACIDS;

ASCT2 PROTEIN; CARRIER PROTEIN; GLUTAMINE; UNCLASSIFIED DRUG; AMINO ACID TRANSPORTER; MINOR HISTOCOMPATIBILITY ANTIGEN; PROTEIN BINDING; SLC1A5 PROTEIN, HUMAN;

ARTICLE; BINDING SITE; CELL PROLIFERATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; LIGAND BINDING; MELANOMA CELL LINE; MOLECULAR DOCKING; MOLECULAR MODEL; PROCESS DEVELOPMENT; PROCESS OPTIMIZATION; PROTEIN CONFORMATION; PROTEIN TARGETING; SCREENING TEST; STRUCTURAL HOMOLOGY; STRUCTURE ANALYSIS; VIRTUAL REALITY; ALGORITHM; AMINO ACID SEQUENCE; CHEMICAL MODEL; CHEMISTRY; MOLECULAR GENETICS; PRECLINICAL STUDY; PROCEDURES; PROTEIN ANALYSIS; SEQUENCE ANALYSIS; SEQUENCE HOMOLOGY; ULTRASTRUCTURE;

ALGORITHMS; AMINO ACID SEQUENCE; AMINO ACID TRANSPORT SYSTEM ASC; BINDING SITES; DRUG EVALUATION, PRECLINICAL; MINOR HISTOCOMPATIBILITY ANTIGENS; MODELS, CHEMICAL; MOLECULAR DOCKING SIMULATION; MOLECULAR SEQUENCE DATA; PROTEIN BINDING; PROTEIN INTERACTION MAPPING; SEQUENCE ANALYSIS, PROTEIN; SEQUENCE HOMOLOGY, AMINO ACID;

EID: 84946045408     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1004477     Document Type: Article

References (62)

1. Kanai Y, Clemencon B, Simonin A, Leuenberger M, Lochner M, et al. (2013) The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Aspects Med 34: 108–120. doi: 10.1016/j.mam.2013.01.001 23506861
2. Fuchs BC, Bode BP, (2005) Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol 15: 254–266. 15916903
3. Ren P, Yue M, Xiao D, Xiu R, Gan L, et al. (2015) ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation. J Pathol 235: 90–100. doi: 10.1002/path.4429 25142020
4. Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, et al. (2013) SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res 19: 560–570. doi: 10.1158/1078-0432.CCR-12-2334 23213057
5. Wang Q, Hardie RA, Hoy AJ, van Geldermalsen M, Gao D, et al. (2015) Targeting ASCT2-Mediated Glutamine Uptake Blocks Prostate Cancer Growth and Tumour Development. J Pathol 236: 278–89 doi: 10.1002/path.4518 25693838
6. Wang Q, Beaumont KA, Otte NJ, Font J, Bailey CG, et al. (2014) Targeting glutamine transport to suppress melanoma cell growth. Int J Cancer 135: 1060–1071. doi: 10.1002/ijc.28749 24531984
7. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, et al. (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136: 521–534. doi: 10.1016/j.cell.2008.11.044 19203585
8. Wang Q, Tiffen J, Bailey CG, Lehman ML, Ritchie W, et al. (2013) Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development. J Natl Cancer Inst 105: 1463–1473. doi: 10.1093/jnci/djt241 24052624
9. Schlessinger A, Khuri N, Giacomini KM, Sali A, (2013) Molecular Modeling and Ligand Docking for Solute Carrier (SLC) Transporters. Curr Top Med Chem 13: 843–856. 23578028
10. Yernool D, Boudker O, Jin Y, Gouaux E, (2004) Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature 431: 811–818. 15483603
11. Boudker O, Ryan RM, Yernool D, Shimamoto K, Gouaux E, (2007) Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature 445: 387–393. 17230192
12. Schlessinger A, Yee SW, Sali A, Giacomini KM, (2013) SLC Classification: An Update. Clin Pharmacol Ther 94: 19–23. doi: 10.1038/clpt.2013.73 23778706
13. Qu S, Kanner BI, (2008) Substrates and non-transportable analogues induce structural rearrangements at the extracellular entrance of the glial glutamate transporter GLT-1/EAAT2. J Biol Chem 283: 26391–26400. doi: 10.1074/jbc.M802401200 18658151
14. Albers T, Marsiglia W, Thomas T, Gameiro A, Grewer C, (2012) Defining substrate and blocker activity of alanine-serine-cysteine transporter 2 (ASCT2) Ligands with Novel Serine Analogs. Molecular Pharmacology 81: 356–365. doi: 10.1124/mol.111.075648 22113081
15. Scopelliti AJ, Ryan RM, Vandenberg RJ, (2013) Molecular determinants for functional differences between alanine-serine-cysteine transporter 1 and other glutamate transporter family members. J Biol Chem 288: 8250–8257. doi: 10.1074/jbc.M112.441022 23393130
16. Georgieva ER, Borbat PP, Ginter C, Freed JH, Boudker O, (2013) Conformational ensemble of the sodium-coupled aspartate transporter. Nat Struct Mol Biol 20: 215–221. doi: 10.1038/nsmb.2494 23334289
17. Stolzenberg S, Khelashvili G, Weinstein H, (2012) Structural intermediates in a model of the substrate translocation path of the bacterial glutamate transporter homologue GltPh. J Phys Chem B 116: 5372–5383. doi: 10.1021/jp301726s 22494242
18. Crisman TJ, Qu S, Kanner BI, Forrest LR, (2009) Inward-facing conformation of glutamate transporters as revealed by their inverted-topology structural repeats. Proc Natl Acad Sci U S A 106: 20752–20757. doi: 10.1073/pnas.0908570106 19926849
19. Jardetzky O, (1966) Simple allosteric model for membrane pumps. Nature 211: 969–970. 5968307
20. Reyes N, Ginter C, Boudker O, (2009) Transport mechanism of a bacterial homologue of glutamate transporters. Nature 462: 880–885. doi: 10.1038/nature08616 19924125
21. Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, et al. (2011) Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol 7: 769–778. doi: 10.1038/nchembio.662 21926995
22. Geier EG, Schlessinger A, Fan H, Gable JE, Irwin JJ, et al. (2013) Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1. Proc Natl Acad Sci U S A 110: 5480–5485. doi: 10.1073/pnas.1218165110 23509259
23. Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, et al. (2011) Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc Natl Acad Sci U S A 108: 15810–15815. doi: 10.1073/pnas.1106030108 21885739
24. Ung PM, Schlessinger A, (2015) DFGmodel: predicting protein kinase structures in inactive states for structure-based discovery of type-II inhibitors. ACS Chem Biol 10: 269–278. doi: 10.1021/cb500696t 25420233
25. Sali A, Blundell TL, (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779–815. 8254673
26. Krivov GG, Shapovalov MV, Dunbrack RL, Jr. (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins 77: 778–795. doi: 10.1002/prot.22488 19603484
27. Hess B, Kutzner C, van der Spoel D, Lindahl E, (2008) GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. Journal of Chemical Theory and Computation 4: 435–447.
28. Fan H, Irwin JJ, Webb BM, Klebe G, Shoichet BK, et al. (2009) Molecular docking screens using comparative models of proteins. J Chem Inf Model 49: 2512–2527. doi: 10.1021/ci9003706 19845314
29. Irwin JJ, Shoichet BK, (2005) ZINC—a free database of commercially available compounds for virtual screening. J Chem Inf Model 45: 177–182. 15667143
30. Kanehisa M, Goto S, (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28: 27–30. 10592173
31. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, et al. (2014) Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res 42: D199–205. doi: 10.1093/nar/gkt1076 24214961
32. Kuntz ID, (1992) Structure-based strategies for drug design and discovery. Science 257: 1078–1082. 1509259
33. Shoichet BK, (2004) Virtual screening of chemical libraries. Nature 432: 862–865. 15602552
34. Broer A, Wagner C, Lang F, Broer S, (2000) Neutral amino acid transporter ASCT2 displays substrate-induced Na+ exchange and a substrate-gated anion conductance. Biochemical Journal 346: 705–710. 10698697
35. Grewer C, Grabsch E, (2004) New inhibitors for the neutral amino acid transporter ASCT2 reveal its Na+-dependent anion leak. J Physiol 557: 747–759. 15107471
36. Grewer C, Grabsch E, (2004) New inhibitors for the neutral amino acid transporter ASCT2 reveal its Na+-dependent anion leak. The Journal of physiology 557: 747–759. 15107471
37. Watzke N, Grewer C, (2001) The anion conductance of the glutamate transporter EAAC1 depends on the direction of glutamate transport. FEBS Lett 503: 121–125. 11513867
38. Bridges RJ, Esslinger CS, (2005) The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacol Ther 107: 271–285. 16112332
39. Zander CB, Albers T, Grewer C, (2013) Voltage-dependent processes in the electroneutral amino acid exchanger ASCT2. J Gen Physiol 141: 659–672. doi: 10.1085/jgp.201210948 23669717
40. Muller K, Faeh C, Diederich F, (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 317: 1881–1886. 17901324
41. Anighoro A, Bajorath J, Rastelli G, (2014) Polypharmacology: challenges and opportunities in drug discovery. J Med Chem 57: 7874–7887. doi: 10.1021/jm5006463 24946140
42. Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM, (2012) Highlights from the international transporter consortium second workshop. Clinical pharmacology and therapeutics 92: 553–556. doi: 10.1038/clpt.2012.126 23085880
43. Traynor K, (2013) Canagliflozin approved for type 2 diabetes. Am J Health Syst Pharm 70: 834.
44. Pei J, Kim BH, Grishin NV, (2008) PROMALS3D: a tool for multiple protein sequence and structure alignments. Nucleic acids research 36: 2295–2300. doi: 10.1093/nar/gkn072 18287115
45. Schrodinger, LLC (2010) The PyMOL Molecular Graphics System, Version 1.3r1.
46. Shen MY, Sali A, (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15: 2507–2524. 17075131
47. Eramian D, Eswar N, Shen MY, Sali A, (2008) How well can the accuracy of comparative protein structure models be predicted? Protein Sci 17: 1881–1893. doi: 10.1110/ps.036061.108 18832340
48. Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, et al. (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins 78: 1950–1958. doi: 10.1002/prot.22711 20408171
49. Shaw DE, Maragakis P, Lindorff-Larsen K, Piana S, Dror RO, et al. (2010) Atomic-level characterization of the structural dynamics of proteins. Science 330: 341–346. doi: 10.1126/science.1187409 20947758
50. Hess B, (2007) P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation. J Chem Theory Comput 4: 116–122.
51. Coleman RG, Carchia M, Sterling T, Irwin JJ, Shoichet BK, (2013) Ligand pose and orientational sampling in molecular docking. PLoS One 8: e75992. doi: 10.1371/journal.pone.0075992 24098414
52. Schlessinger A, Geier E, Fan H, Irwin JJ, Shoichet BK, et al. (2011) Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc Natl Acad Sci U S A 108: 15810–15815. doi: 10.1073/pnas.1106030108 21885739
53. Schlessinger A, Wittwer MB, Dahlin A, Khuri N, Bonomi M, et al. (2012) High Selectivity of the gamma-Aminobutyric Acid Transporter 2 (GAT-2, SLC6A13) Revealed by Structure-based Approach. Journal of Biological Chemistry 287: 37745–37756. doi: 10.1074/jbc.M112.388157 22932902
54. Huang N, Shoichet BK, Irwin JJ, (2006) Benchmarking sets for molecular docking. J Med Chem 49: 6789–6801. 17154509
55. Kekuda R, Prasad PD, Fei YJ, Torres-Zamorano V, Sinha S, et al. (1996) Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter Bo from a human placental choriocarcinoma cell line. J Biol Chem 271: 18657–18661. 8702519
56. (2010) The Universal Protein Resource (UniProt) in 2010. Nucleic Acids Res 38: D142–148. doi: 10.1093/nar/gkp846 19843607
57. Mysinger MM, Carchia M, Irwin JJ, Shoichet BK, (2012) Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem 55: 6582–6594. doi: 10.1021/jm300687e 22716043
58. McGann M, (2011) FRED pose prediction and virtual screening accuracy. J Chem Inf Model 51: 578–596. doi: 10.1021/ci100436p 21323318
59. Carr RA, Congreve M, Murray CW, Rees DC, (2005) Fragment-based lead discovery: leads by design. Drug Discov Today. 10: 987–992. 16023057
60. Broer A, Brookes N, Ganapathy V, Dimmer KS, Wagner CA, et al. (1999) The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux. J Neurochem 73: 2184–2194. 10537079
61. Watzke N, Bamberg E, Grewer C, (2001) Early intermediates in the transport cycle of the neuronal excitatory amino acid carrier EAAC1. J Gen Physiol 117: 547–562. 11382805
62. Wang Q, Bailey CG, Ng C, Tiffen J, Thoeng A, et al. (2011) Androgen receptor and nutrient signaling pathways coordinate the demand for increased amino acid transport during prostate cancer progression. Cancer Res 71: 7525–7536. doi: 10.1158/0008-5472.CAN-11-1821 22007000