SLC Transporters: Structure, Function, and Drug Discovery.
The human Solute Carrier (SLC) transporters are important targets for drug development. Structure-based drug discovery for SLC transporters requires the description of their structure, dynamics, and mechanism of interaction with small molecule ligands and ions. The recent determination of atomic structures of human SLC transporters and their homologs, combined with improved computational power and prediction methods have led to an increased applicability of structure-based drug design methods for human SLC members. In this review, we provide an overview of the SLC transporters' structures and transport mechanisms. We then describe computational techniques, such as homology modeling and virtual screening that are emerging as key tools to discover chemical probes for human SLC members. We illustrate the utility of these methods by presenting case studies in which rational integration of computation and experiment was used to characterize SLC members that transport key nutrients and metabolites, including the amino acid transporters LAT-1 and ASCT2, the SLC13 family of citric acid cycle intermediate transporters, and the glucose transporter GLUT1. We conclude with a brief discussion about future directions in structure-based drug discovery for the human SLC superfamily, one of the most structurally and functionally diverse protein families in human.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Claire
C
Colas
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Peter Man-Un
PM
Ung
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Avner
A
Schlessinger
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W423-6
18477636
Pathol Int. 2009 Jan;59(1):7-18
19121087
Int J Mol Sci. 2015 Sep 22;16(9):22830-55
26402672
Cell Chem Biol. 2016 Feb 18;23(2):211-213
26971872
J Gen Physiol. 1927 Mar 7;8(6):519-30
19872213
Chem Sci. 2014 Dec 1;6(1):237-245
25580214
PLoS Comput Biol. 2015 Oct 07;11(10):e1004477
26444490
Protein Eng. 1994 Mar;7(3):385-91
8177887
J Gen Physiol. 2014 Jun;143(6):745-59
24821967
Pflugers Arch. 2004 Feb;447(5):465-8
14624363
Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E141-5
20009031
Nature. 2012 Nov 22;491(7425):622-6
23086149
Sci Transl Med. 2011 Aug 3;3(94):94ra70
21813754
Adv Drug Deliv Rev. 2006 Nov 30;58(12-13):1431-50
17097188
Nat Commun. 2014 Aug 04;5:4521
25088546
Brain. 2015 Nov;138(Pt 11):3238-50
26384929
Oncogene. 2016 Jun 16;35(24):3201-8
26455325
Science. 2015 Nov 6;350(6261):680-4
26542571
Cell. 2011 Mar 4;144(5):646-74
21376230
Mol Aspects Med. 2013 Apr-Jun;34(2-3):183-96
23506865
Nat Chem Biol. 2011 Sep 18;7(11):769-78
21926995
Chem Biol Drug Des. 2006 Jan;67(1):83-4
16492153
Science. 2008 Dec 12;322(5908):1655-61
19074341
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12079-84
10518579
J Biol Chem. 2008 Oct 17;283(42):28680-90
18678877
Annu Rev Biophys Biomol Struct. 2000;29:291-325
10940251
Nature. 2005 Sep 8;437(7056):215-23
16041361
Elife. 2014 May 19;3:e02283
24842876
J Mol Biol. 1993 Dec 5;234(3):779-815
8254673
Cell. 2015 Jul 30;162(3):478-87
26232220
Nat Rev Drug Discov. 2010 Mar;9(3):215-36
20190787
Mol Pharmacol. 2012 Mar;81(3):356-65
22113081
J Clin Invest. 2008 Jun;118(6):2157-68
18451999
Nat Biotechnol. 2011 Apr;29(4):335-40
21478852
Biochemistry. 2011 Nov 15;50(45):9684-93
21995338
Pflugers Arch. 2004 Feb;447(5):532-42
14770310
Cancer Res. 2011 Dec 15;71(24):7525-36
22007000
J Mol Biol. 2011 Apr 15;407(5):698-715
21315728
Protein Sci. 2006 Nov;15(11):2507-24
17075131
J Med Chem. 2015 Mar 12;58(5):2149-58
25679268
Methods Enzymol. 2015;557:167-98
25950965
Drug Discov Today. 2015 Nov;20(11):1355-64
26303408
Cancer Lett. 2007 Nov 18;257(2):244-51
17910902
Am J Physiol. 1988 Dec;255(6 Pt 2):F1170-7
3202180
J Chem Inf Model. 2010 Sep 27;50(9):1561-73
20735049
Front Chem. 2014 Aug 11;2:61
25157349
Curr Opin Struct Biol. 2015 Apr;31:96-105
25913536
Nature. 2014 Jun 5;510(7503):121-5
24847886
J Med Chem. 2012 Jul 26;55(14):6582-94
22716043
Nature. 2010 Feb 11;463(7282):828-32
20090677
Mol Aspects Med. 2013 Apr-Jun;34(2-3):139-58
23506863
PLoS Comput Biol. 2015 Oct 20;11(10):e1004551
26485255
J Med Chem. 2013 Feb 14;56(3):781-795
23241029
Nature. 2009 Dec 17;462(7275):880-5
19924125
J Endocrinol. 2008 Jul;198(1):157-68
18469022
Biochem Biophys Res Commun. 2002 Dec 6;299(3):465-71
12445824
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W246-51
24753425
Nature. 2007 Jan 25;445(7126):387-93
17230192
Sci Rep. 2015 Dec 01;5:17391
26620127
J Chem Inf Model. 2011 Mar 28;51(3):578-96
21323318
Int J Endocrinol. 2010;2010:
20706540
Clin Pharmacol Ther. 2013 Jul;94(1):19-23
23778706
Protein Sci. 2010 Mar;19(3):412-28
20052679
Bioconjug Chem. 2010 Nov 17;21(11):2038-48
20968316
Nature. 2004 Dec 16;432(7019):862-5
15602552
Am J Physiol Cell Physiol. 2015 May 15;308(10):C827-34
25715702
J Phys Chem B. 2013 May 9;117(18):5486-96
23590433
Proteins. 2003 Sep 1;52(4):609-23
12910460
Nature. 2004 Oct 14;431(7010):811-8
15483603
Pflugers Arch. 2014 Jan;466(1):119-30
24114175
Curr Top Med Chem. 2013;13(7):843-56
23578028
Science. 1993 Mar 5;259(5100):1445-50
8451640
Nature. 2013 Nov 7;503(7474):85-90
24037379
Science. 2009 May 22;324(5930):1029-33
19460998
Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15810-5
21885739
Proteins. 2009 Dec;77(4):778-95
19603484
J Biol Chem. 2012 Nov 2;287(45):37745-56
22932902
ACS Chem Neurosci. 2015 Nov 18;6(11):1892-900
26389667
Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1784-8
24453216
J Biol Chem. 2014 Jun 20;289(25):17468-79
24808181
J Natl Cancer Inst. 2013 Oct 2;105(19):1463-73
24052624
Adv Pharmacol. 2011;62:1-36
21907905
J Am Chem Soc. 2012 Jan 11;134(1):453-63
22092197
Am J Physiol Endocrinol Metab. 2009 Oct;297(4):E836-48
19690067
Cancer Sci. 2012 Feb;103(2):382-9
22077314
J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
15667143
J Nucl Med. 2006 Jun;47(6):901-3
16741296
Nature. 2012 Oct 18;490(7420):361-6
23075985
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9638-43
20457942
Cell. 2009 Feb 6;136(3):521-34
19203585
Nat Struct Mol Biol. 2013 Jun;20(6):766-8
23624861
Adv Drug Deliv Rev. 2007 Aug 10;59(8):748-58
17659804
Nature. 2015 Oct 15;526(7573):397-401
26416735
Science. 2004 Mar 19;303(5665):1813-8
15031495
Bioinformatics. 2010 Dec 15;26(24):3067-74
20947525
Cell Metab. 2011 Aug 3;14(2):184-95
21803289
Clin Pharmacol Ther. 2011 Nov;90(5):674-84
21956618
Nat Commun. 2014 Apr 03;5:3608
24699711
Pflugers Arch. 2004 Feb;447(5):666-76
12883891
J Biol Chem. 2013 Mar 22;288(12):8250-8257
23393130
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2589-94
19202063
Cell Chem Biol. 2016 Feb 18;23(2):299-309
27028887
J Pathol. 2015 Jul;236(3):278-89
25693838
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5480-5
23509259
Free Radic Biol Med. 2012 Feb 15;52(4):735-46
22206977
Curr Top Membr. 2012;70:1-28
23177982
J Physiol. 2014 Mar 1;592(5):863-9
23878376
EMBO Rep. 2012 Sep;13(9):861-6
22836580
J Membr Biol. 2011 Jan;239(1-2):85-93
21161516
Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5517-22
22431600
Nat Struct Mol Biol. 2012 Feb 12;19(3):355-7
22343718
Am J Physiol. 1999 Jan;276(1):E1-E18
9886945
J Chem Inf Model. 2009 Nov;49(11):2512-27
19845314
PLoS Comput Biol. 2013;9(2):e1002909
23436987
Nat Rev Drug Discov. 2015 Aug;14(8):543-60
26111766
Semin Cancer Biol. 2005 Aug;15(4):254-66
15916903
EMBO J. 2011 Jan 19;30(2):417-26
21131908
EMBO J. 2002 Feb 15;21(4):580-9
11847106
J Biol Chem. 2010 Jun 4;285(23):17725-33
20378543
J Med Chem. 2012 Sep 13;55(17):7828-40
22889351
Nat Genet. 1998 Feb;18(2):188-91
9462754
Science. 1985 Sep 6;229(4717):941-5
3839598
J Med Chem. 2005 Jun 16;48(12):4040-8
15943477
Physiology (Bethesda). 2009 Dec;24:377-86
19996368
Methods Mol Biol. 2013;924:361-405
23034756
Biochemistry. 2015 Aug 11;54(31):4900-8
26176240
J Mol Biol. 1990 Oct 5;215(3):403-10
2231712
J Biol Chem. 2014 Jun 13;289(24):16998-7008
24808185
Nature. 2015 Oct 15;526(7573):391-6
26176916
Am J Physiol Cell Physiol. 2012 Sep 1;303(5):C530-9
22673619
J Histochem Cytochem. 1992 Feb;40(2):193-9
1552163
Nucleic Acids Res. 2008 Apr;36(7):2295-300
18287115