How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations

Song, Lin Frank; Rabara, Dana; Bali, Semiha K.; Pei, Jun; Lau, Edmond Y.; Kirshner, Dan; Lightstone, Felice C.; McCormick, Frank; Stephen, Andrew G.; Yang, Yue

doi:10.1021/acs.jcim.5c02061

Title: How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations

Journal Article · Mon Nov 24 00:00:00 UTC 2025 · Journal of Chemical Information and Modeling

DOI: https://doi.org/10.1021/acs.jcim.5c02061 · OSTI ID:3013995

Song, Lin Frank ^[1]; Rabara, Dana ^[2];

^[3]; Pei, Jun ^[3]; Lau, Edmond Y. ^[3]; Kirshner, Dan ^[3]; Lightstone, Felice C. ^[3]; McCormick, Frank ^[4];

^[2]; Yang, Yue ^[5]

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Westlake Pharmaceuticals, Hangzhou (China)
Frederick National Laboratory for Cancer Research, Frederick, MD (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Frederick National Laboratory for Cancer Research, Frederick, MD (United States); Univ. of California, San Francisco, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); BridgeBio Inc., Palo Alto, CA (United States)

Oncogenic KRAS mutations impair GTP hydrolysis and increase the active GTP-bound KRAS population, which leads to growth-factor-independent cell proliferation and survival of cancer cells. Despite notable successes of small-molecule inhibitors in the treatment of KRASG12C cancer, many of these small-molecule inhibitors preferentially bind to inactive (GDP-bound) mutant KRAS, whose availability is limited by the slow rate of intrinsic GTP hydrolysis. A better understanding of how KRAS mutations impair intrinsic hydrolysis is important for designing more effective small-molecule therapeutics. In this work, experimental and computational approaches were utilized to investigate how the most important oncogenic mutations affect the intrinsic hydrolysis of GTP. Here, we found that Q61H, G12V, and G12R mutations impair intrinsic hydrolysis by around 7-fold, 9-fold, and more than 20-fold, respectively, whereas G12A, G12C, G12D, and G13D have less effect. Based on mechanistic investigations, we propose that KRAS mutations impair intrinsic hydrolysis by disrupting the interactions needed to align the nucleophilic water molecule with GTP for nucleophilic attack. These results can assist small-molecule inhibitor design and also benefit the development of other therapeutic strategies, such as rescuing hydrolysis.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 3013995

Report Number(s):: LLNL--JRNL-849961

Journal Information:: Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 23 Vol. 65; ISSN 1549-9596; ISSN 1549-960X

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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cancer
computation
enzyme mechanism
enzyme mutation
intrinsic GTP hydrolysis

Title: How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations

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