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Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.
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- Additional Information
- Source:
Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE
- Publication Information:
Publication: Washington, DC : American Chemical Society
Original Publication: Easton, Pa. [etc.]
- Subject Terms:
- Abstract:
Ras GTPases play a crucial role in cell signaling pathways. Mutations of the Ras gene occur in about one third of cancerous cell lines and are often associated with detrimental clinical prognosis. Hot spot residues Gly12, Gly13, and Gln61 cover 97% of oncogenic mutations, which impair the enzymatic activity in Ras. Using QM/MM free energy calculations, we present a two-step mechanism for the GTP hydrolysis catalyzed by the wild-type Ras.GAP complex. We found that the deprotonation of the catalytic water takes place via the Gln61 as a transient Brønsted base. We also determined the reaction profiles for key oncogenic Ras mutants G12D and G12C using QM/MM minimizations, matching the experimentally observed loss of catalytic activity, thereby validating our reaction mechanism. Using the optimized reaction paths, we devised a fast and accurate procedure to design GAP mutants that activate G12D Ras. We replaced GAP residues near the active site and determined the activation barrier for 190 single mutants. We furthermore built a machine learning for ultrafast screening, by fast prediction of the barrier heights, tested both on the single and double mutations. This work demonstrates that fast and accurate screening can be accomplished via QM/MM reaction path optimizations to design protein sequences with increased catalytic activity. Several GAP mutations are predicted to re-enable catalysis in oncogenic G12D, offering a promising avenue to overcome aberrant Ras-driven signal transduction by activating enzymatic activity instead of inhibition. The outlined computational screening protocol is readily applicable for designing ligands and cofactors analogously.
- References:
Cancer Discov. 2014 Dec;4(12):1418-29. (PMID: 25252692)
Genes (Basel). 2021 Jun 10;12(6):. (PMID: 34200676)
Nature. 2019 Nov;575(7781):217-223. (PMID: 31666701)
J Biol Chem. 2018 Mar 16;293(11):3871-3879. (PMID: 29382720)
Nat Struct Mol Biol. 2021 Oct;28(10):847-857. (PMID: 34625747)
Cell Logist. 2017 Jun 23;7(3):e1340104. (PMID: 28944094)
Biochemistry. 1992 Sep 22;31(37):8691-6. (PMID: 1390653)
Phys Chem Chem Phys. 2019 Jan 2;21(2):859-867. (PMID: 30556562)
Br J Cancer. 2015 Jan 20;112(2):217-26. (PMID: 25180764)
Chem Sci. 2021 May 4;12(23):8178-8189. (PMID: 34194708)
J Chem Phys. 2023 Mar 7;158(9):091104. (PMID: 36889947)
Mol Cancer Res. 2015 Sep;13(9):1325-35. (PMID: 26037647)
RSC Adv. 2022 Jan 11;12(3):1742-1757. (PMID: 35425180)
Cell Signal. 2014 Sep;26(9):1950-7. (PMID: 24863881)
Acc Chem Res. 2017 Mar 21;50(3):561-566. (PMID: 28945421)
EMBO J. 1990 Aug;9(8):2351-9. (PMID: 2196171)
Cancer. 2012 Aug 15;118(16):4014-23. (PMID: 22180178)
Science. 1997 Jul 18;277(5324):333-8. (PMID: 9219684)
Biochemistry. 2017 Mar 14;56(10):1482-1497. (PMID: 28225609)
Br J Cancer. 2013 Apr 30;108(8):1757-64. (PMID: 23511557)
Cell. 1990 Aug 10;62(3):539-48. (PMID: 2199064)
Chem Sci. 2020 Aug 19;11(34):9272-9289. (PMID: 34094198)
Chem Sci. 2020 Nov 27;12(4):1433-1444. (PMID: 34163906)
Mol Cell Biol. 2004 Sep;24(18):7965-75. (PMID: 15340059)
Cancer Treat Rev. 2021 Sep;99:102238. (PMID: 34098219)
Nat Rev Drug Discov. 2014 Nov;13(11):828-51. (PMID: 25323927)
J Phys Chem B. 2019 May 9;123(18):3935-3944. (PMID: 30991803)
Phys Chem Chem Phys. 2018 Oct 7;20(37):23827-23836. (PMID: 30202846)
Chemistry. 2019 Jun 26;25(36):8484-8488. (PMID: 31038818)
Nat Rev Drug Discov. 2022 Dec;21(12):881-898. (PMID: 36008483)
Nat Chem. 2021 Oct;13(10):1017-1022. (PMID: 34413499)
J Am Chem Soc. 2016 Nov 16;138(45):15035-15045. (PMID: 27740761)
Science. 1990 Aug 10;249(4969):655-9. (PMID: 2116665)
Biochem Soc Trans. 2012 Dec 1;40(6):1404-8. (PMID: 23176489)
Biochem Biophys Res Commun. 2020 Feb 12;522(3):690-696. (PMID: 31787238)
Biophys J. 2012 Jan 4;102(1):152-7. (PMID: 22225809)
PLoS One. 2015 Sep 14;10(9):e0138002. (PMID: 26368812)
Mol Cell Biol. 1992 May;12(5):2050-6. (PMID: 1569940)
Chem Soc Rev. 2016 Sep 21;45(18):4929-52. (PMID: 27396271)
Curr Opin Struct Biol. 2020 Apr;61:198-206. (PMID: 32065923)
Biol Chem. 2019 Dec 18;401(1):143-163. (PMID: 31600136)
PLoS Comput Biol. 2018 Sep 10;14(9):e1006458. (PMID: 30199525)
Biochemistry. 1994 Mar 22;33(11):3237-44. (PMID: 8136358)
Proteins. 2007 Feb 1;66(2):456-66. (PMID: 17094109)
Arch Biochem Biophys. 2015 Sep 15;582:80-90. (PMID: 25731854)
EMBO J. 2008 Apr 9;27(7):1145-53. (PMID: 18309292)
J Exp Clin Cancer Res. 2022 Jan 19;41(1):27. (PMID: 35045886)
Biopolymers. 2016 Aug;105(8):431-48. (PMID: 26972107)
J Am Chem Soc. 2006 Nov 29;128(47):15310-23. (PMID: 17117884)
Mol Cell. 2022 Mar 3;82(5):950-968.e14. (PMID: 35202574)
Biochim Biophys Acta. 2013 Dec;1834(12):2679-90. (PMID: 24056041)
Br J Cancer. 2021 Feb;124(4):797-804. (PMID: 33208919)
Cancer Discov. 2016 Mar;6(3):316-29. (PMID: 26739882)
J Phys Chem B. 2021 Aug 12;125(31):8805-8813. (PMID: 34324329)
Biochem J. 2023 Jan 13;480(1):1-23. (PMID: 36607281)
Front Pharmacol. 2017 Nov 14;8:823. (PMID: 29184501)
Eur J Med Chem. 2021 Dec 15;226:113816. (PMID: 34520956)
Biophys J. 2018 Oct 16;115(8):1417-1430. (PMID: 30224050)
Biochemistry. 2014 Nov 18;53(45):7093-9. (PMID: 25339142)
Molecules. 2021 Jun 30;26(13):. (PMID: 34208932)
Mol Cancer Res. 2022 Jan;20(1):30-44. (PMID: 34462329)
J Chem Inf Model. 2021 Oct 25;61(10):5212-5222. (PMID: 34570515)
Biochemistry. 2013 Nov 26;52(47):8465-79. (PMID: 24224811)
Curr Opin Struct Biol. 2021 Apr;67:212-218. (PMID: 33517098)
ACS Pharmacol Transl Sci. 2021 Feb 04;4(2):703-712. (PMID: 33860195)
Cancer Res. 2021 Jul 15;81(14):3849-3861. (PMID: 33903121)
Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20509-14. (PMID: 24282301)
Br J Cancer. 2019 Jul;121(3):197-198. (PMID: 31239544)
Comput Struct Biotechnol J. 2020 Apr 09;18:1000-1011. (PMID: 32373288)
Pituitary. 2021 Oct;24(5):746-753. (PMID: 33954928)
Arch Biochem Biophys. 2015 Sep 15;582:68-79. (PMID: 25797438)
Nature. 2013 Nov 28;503(7477):548-51. (PMID: 24256730)
J Biol Chem. 2015 Oct 2;290(40):24079-90. (PMID: 26272610)
Cancers (Basel). 2021 Aug 13;13(16):. (PMID: 34439225)
Angew Chem Int Ed Engl. 2016 Mar 1;55(10):3318-22. (PMID: 26822702)
Proteins. 2005 Aug 15;60(3):495-503. (PMID: 15906320)
J Cell Sci. 2016 Apr 1;129(7):1287-92. (PMID: 26985062)
Science. 2021 Oct 08;374(6564):197-201. (PMID: 34618566)
PLoS One. 2020 Oct 16;15(10):e0234836. (PMID: 33064725)
Nat Struct Mol Biol. 2008 Apr;15(4):373-80. (PMID: 18376416)
Mol Cell Biol. 2002 Feb;22(4):1158-71. (PMID: 11809807)
Nat Commun. 2022 Sep 10;13(1):5333. (PMID: 36088370)
- Accession Number:
EC 3.6.5.2 (ras Proteins)
- Publication Date:
Date Created: 20230908 Date Completed: 20230921 Latest Revision: 20230924
- Publication Date:
20240829
- Accession Number:
PMC10515638
- Accession Number:
10.1021/jacs.3c04330
- Accession Number:
37682266
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