Assigning functionality to cysteines by base editing of cancer dependency genes.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
01
02
2023
accepted:
24
08
2023
medline:
30
10
2023
pubmed:
3
10
2023
entrez:
2
10
2023
Statut:
ppublish
Résumé
Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding events affect protein function, however, remains challenging. Here we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cancer cell proliferation. The resulting atlas, which covers more than 13,800 cysteines on more than 1,750 cancer dependency proteins, confirms the essentiality of cysteines targeted by covalent drugs and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines in more than 160 cancer dependency proteins. We further show that a stereoselective and site-specific ligand targeting an essential cysteine in TOE1 inhibits the nuclease activity of this protein through an apparent allosteric mechanism. Our findings thus describe a versatile method and valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.
Identifiants
pubmed: 37783940
doi: 10.1038/s41589-023-01428-w
pii: 10.1038/s41589-023-01428-w
pmc: PMC10698195
mid: NIHMS1940695
doi:
Substances chimiques
Cysteine
K848JZ4886
Proteome
0
TOE1 protein, human
0
Nuclear Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1320-1330Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM118069
Pays : United States
Organisme : NHGRI NIH HHS
ID : RM1 HG009490
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231991
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118062
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI142756
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Cancer Discov. 2014 Sep;4(9):1046-61
pubmed: 24893891
Nat Rev Drug Discov. 2004 Apr;3(4):301-17
pubmed: 15060526
RSC Chem Biol. 2021 Feb 9;2(2):354-367
pubmed: 34458789
Science. 2018 Sep 21;361(6408):1259-1262
pubmed: 30166441
Nature. 2021 Aug;596(7873):583-589
pubmed: 34265844
Nature. 2019 Jul;571(7765):408-412
pubmed: 31243370
Nat Struct Mol Biol. 2011 Mar;18(3):316-22
pubmed: 21336276
Nature. 2019 Jul;571(7765):413-418
pubmed: 31243372
Cell Chem Biol. 2023 Jun 15;30(6):683-698.e3
pubmed: 37119813
Nature. 2010 Dec 9;468(7325):790-5
pubmed: 21085121
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Cell Chem Biol. 2023 Jul 20;30(7):828-838.e4
pubmed: 37451266
Curr Opin Chem Biol. 2019 Jun;50:29-36
pubmed: 30897495
Cell. 2020 Aug 20;182(4):1009-1026.e29
pubmed: 32730809
Nat Microbiol. 2022 Nov;7(11):1891-1905
pubmed: 36266336
Nat Chem Biol. 2022 Dec;18(12):1388-1398
pubmed: 36097295
Nat Rev Drug Discov. 2022 Mar;21(3):181-200
pubmed: 35042991
J Med Chem. 2013 May 23;56(10):3996-4016
pubmed: 23634668
Nat Biotechnol. 2022 Jun;40(6):874-884
pubmed: 35411116
Nucleic Acids Res. 2018 Jan 4;46(D1):D213-D217
pubmed: 29069475
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5381-3
pubmed: 1608946
Isr J Chem. 2019 Feb;59(1-2):52-59
pubmed: 31123369
Cancer Cell. 2005 Sep;8(3):255-65
pubmed: 16153896
Genes Dev. 2020 Jul 1;34(13-14):989-1001
pubmed: 32499401
Nat Chem. 2021 Nov;13(11):1081-1092
pubmed: 34504315
Mol Cell. 2023 May 18;83(10):1725-1742.e12
pubmed: 37084731
Nat Protoc. 2021 Feb;16(2):1089-1128
pubmed: 33462442
Nature. 2016 Jun 15;534(7608):570-4
pubmed: 27309814
Acc Chem Res. 2021 Apr 6;54(7):1801-1813
pubmed: 33733731
Cell. 2021 Feb 18;184(4):1064-1080.e20
pubmed: 33606977
Cell. 2017 Oct 19;171(3):696-709.e23
pubmed: 28965760
Cell Rep. 2018 Apr 17;23(3):888-898
pubmed: 29669292
Nat Genet. 2017 Mar;49(3):457-464
pubmed: 28092684
Biochemistry. 2012 Jun 26;51(25):4990-5003
pubmed: 22697260
Nature. 2017 Nov 23;551(7681):464-471
pubmed: 29160308
Nat Biotechnol. 2021 May;39(5):630-641
pubmed: 33398154
Nat Chem Biol. 2023 Feb;19(2):176-186
pubmed: 36266353
Curr Opin Struct Biol. 2022 Aug;75:102396
pubmed: 35636004
Nat Biotechnol. 2019 Sep;37(9):1070-1079
pubmed: 31332326
Nature. 1993 Jul 29;364(6436):412-20
pubmed: 8332212
Nat Biotechnol. 2022 Jun;40(6):862-873
pubmed: 35165384
J Med Chem. 2020 Jan 9;63(1):52-65
pubmed: 31820981
Cancer Cell. 2020 Oct 12;38(4):534-550.e9
pubmed: 32888433
Nat Biotechnol. 2020 Jul;38(7):883-891
pubmed: 32433547
Nat Biotechnol. 2019 Mar;37(3):224-226
pubmed: 30809026
Nature. 2016 Apr 20;533(7603):420-4
pubmed: 27096365
Cell. 2015 Jun 4;161(6):1252-65
pubmed: 26046436
J Clin Oncol. 2018 Mar 20;36(9):859-866
pubmed: 29381435
Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5
pubmed: 24234437
Proc Natl Acad Sci U S A. 2022 Aug 30;119(35):e2208457119
pubmed: 35994671
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Mol Cell Biol. 2007 Mar;27(5):1686-95
pubmed: 17178830
Nature. 2013 Nov 28;503(7477):548-51
pubmed: 24256730
Nat Biotechnol. 2015 Jun;33(6):661-7
pubmed: 25961408