Combining structural and coevolution information to unveil allosteric sites.
Journal
Chemical science
ISSN: 2041-6520
Titre abrégé: Chem Sci
Pays: England
ID NLM: 101545951
Informations de publication
Date de publication:
28 Jun 2023
28 Jun 2023
Historique:
received:
14
11
2022
accepted:
02
06
2023
medline:
30
6
2023
pubmed:
30
6
2023
entrez:
30
6
2023
Statut:
epublish
Résumé
Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets.
Identifiants
pubmed: 37389247
doi: 10.1039/d2sc06272k
pii: d2sc06272k
pmc: PMC10306073
doi:
Types de publication
Journal Article
Langues
eng
Pagination
7057-7067Informations de copyright
This journal is © The Royal Society of Chemistry.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): GLS, HK, LW, PN, KB, JPJ, MS, CJS, CT, AH and AIF are employees of AstraZeneca and own stock options.
Références
Nature. 2017 Jun 8;546(7657):312-315
pubmed: 28514449
J Mol Biol. 2009 Aug 7;391(1):1-11
pubmed: 19501598
Mach Learn Sci Technol. 2021 Sep;2(3):
pubmed: 34396127
Nat Commun. 2016 Aug 26;7:12477
pubmed: 27561351
J Am Chem Soc. 2016 Nov 2;138(43):14257-14263
pubmed: 27726386
J Chem Theory Comput. 2019 May 14;15(5):3331-3343
pubmed: 30998331
Sci Rep. 2018 Mar 1;8(1):3890
pubmed: 29497085
Cell. 2009 Aug 21;138(4):774-86
pubmed: 19703402
Annu Rev Biophys. 2013;42:169-89
pubmed: 23451894
Nat Struct Mol Biol. 2013 Oct;20(10):1182-90
pubmed: 24037507
Curr Opin Struct Biol. 2015 Feb;30:17-24
pubmed: 25500675
J Biotechnol. 2012 Jun 15;159(3):135-44
pubmed: 22326626
PLoS One. 2012;7(7):e39713
pubmed: 22768308
J Med Chem. 2020 Jul 23;63(14):7559-7568
pubmed: 32543856
Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13331-13342
pubmed: 33951246
J Chem Theory Comput. 2014 Apr 8;10(4):1762-9
pubmed: 26580384
Nat Commun. 2020 Jul 31;11(1):3862
pubmed: 32737291
J Mol Biol. 2008 Apr 18;378(1):1-11
pubmed: 18353365
J Chem Inf Model. 2021 Mar 22;61(3):1287-1299
pubmed: 33599485
J Chem Inf Model. 2017 Sep 25;57(9):2358-2363
pubmed: 28825477
Proteins. 2004 Aug 1;56(2):322-37
pubmed: 15211515
PLoS Comput Biol. 2014 Feb 06;10(2):e1003394
pubmed: 24516370
Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9407-9
pubmed: 27512035
Cell. 2011 Dec 23;147(7):1564-75
pubmed: 22196731
Biophys J. 2021 Mar 2;120(5):950-963
pubmed: 33515603
Curr Opin Struct Biol. 2016 Dec;41:159-171
pubmed: 27607077
J Biol Chem. 2023 Mar;299(3):102959
pubmed: 36717078
J Med Chem. 2015 Sep 24;58(18):7140-63
pubmed: 26090771
Biophys J. 2010 Dec 1;99(11):3704-15
pubmed: 21112295
Bioinformatics. 2014 May 1;30(9):1314-5
pubmed: 24413526
Drug Discov Today. 2018 Feb;23(2):359-365
pubmed: 29030241
Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9728-33
pubmed: 23716694
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11218-23
pubmed: 11562470
Mol Syst Biol. 2006;2:36
pubmed: 16820777
Bioinformatics. 2013 Sep 15;29(18):2357-9
pubmed: 23842804
Sci Adv. 2020 Jul 17;6(29):eabb5277
pubmed: 32832645
J Med Chem. 2010 Aug 12;53(15):5858-67
pubmed: 20684613
J Chem Theory Comput. 2016 Nov 8;12(11):5563-5574
pubmed: 27682200
Phys Biol. 2005 Nov 09;2(4):S137-47
pubmed: 16280619
J Med Chem. 2019 Jul 25;62(14):6405-6421
pubmed: 30817889
Nat Rev Genet. 2013 Apr;14(4):249-61
pubmed: 23458856
PLoS Comput Biol. 2016 Mar 10;12(3):e1004620
pubmed: 26964042
Phys Biol. 2013 Oct;10(5):056013
pubmed: 24104456
Proteins. 2002 Aug 1;48(2):227-41
pubmed: 12112692
Eur Biophys J. 1984;11(2):103-9
pubmed: 6544679
ACS Chem Biol. 2016 Jun 17;11(6):1693-701
pubmed: 27028906
Nat Struct Biol. 2003 Jan;10(1):59-69
pubmed: 12483203
Biochem J. 2010 Aug 1;429(3):403-17
pubmed: 20626350
Curr Opin Struct Biol. 2004 Dec;14(6):706-15
pubmed: 15582395
J Chem Theory Comput. 2009 Sep 8;5(9):2486-2502
pubmed: 20161451
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15711-6
pubmed: 17898174
Chem Biol. 2015 Jun 18;22(6):689-703
pubmed: 26091166
J Chem Inf Model. 2021 Jul 26;61(7):3667-3680
pubmed: 34156843
J Chem Theory Comput. 2017 Dec 12;13(12):6343-6357
pubmed: 29112408
Nat Commun. 2014;5:3287
pubmed: 24518821
Essays Biochem. 2017 Nov 8;61(5):485-493
pubmed: 29118095
Chem Rev. 2016 Jun 8;116(11):6370-90
pubmed: 27074285
Acc Chem Res. 2020 Mar 17;53(3):654-661
pubmed: 32134250
Front Mol Biosci. 2020 Jul 09;7:136
pubmed: 32733918
ACS Cent Sci. 2017 Sep 27;3(9):949-960
pubmed: 28979936
Chem Rev. 2016 Jun 8;116(11):6263-6
pubmed: 27268255
Cell Chem Biol. 2019 Jan 17;26(1):9-15
pubmed: 30482678
Chem Rev. 2016 Jun 8;116(11):6463-87
pubmed: 26894745
Curr Opin Cell Biol. 2012 Feb;24(1):107-15
pubmed: 22129583
Arch Biochem Biophys. 2013 Oct 1;538(1):6-15
pubmed: 23933229
Curr Opin Pharmacol. 2010 Dec;10(6):715-22
pubmed: 20884293
FASEB J. 2019 Oct;33(10):11507-11527
pubmed: 31345061