Academic Journal
Dynamic conformational equilibria in the active states of KRAS and NRAS.
| Τίτλος: | Dynamic conformational equilibria in the active states of KRAS and NRAS. |
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| Συγγραφείς: | Rennella E; University of Toronto, Department of Biochemistry Toronto Canada., Henry C; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Dickson CJ; Novartis Biomedical Research Cambridge MA USA., Georgescauld F; Northeastern University, Department of Chemistry and Chemical Biology Boston MA USA., Wales TE; Northeastern University, Department of Chemistry and Chemical Biology Boston MA USA., Erdmann D; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Cotesta S; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Maira M; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Sedrani R; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Brachmann SM; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Ostermann N; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Engen JR; Northeastern University, Department of Chemistry and Chemical Biology Boston MA USA., Kay LE; University of Toronto, Department of Biochemistry Toronto Canada., Beyer KS; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Wilcken R; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com., Jahnke W; Novartis Biomedical Research Basel Switzerland wolfgang.jahnke@novartis.com rwilcken@flaretx.com kim.beyer@novartis.com. |
| Πηγή: | RSC chemical biology [RSC Chem Biol] 2024 Nov 25; Vol. 6 (1), pp. 106-118. Date of Electronic Publication: 2024 Nov 25 (Print Publication: 2025). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Royal Society of Chemistry Country of Publication: England NLM ID: 101768727 Publication Model: eCollection Cited Medium: Internet ISSN: 2633-0679 (Electronic) Linking ISSN: 26330679 NLM ISO Abbreviation: RSC Chem Biol Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: Cambridge : Royal Society of Chemistry, [2020]- |
| Περίληψη: | The design of potent RAS inhibitors benefits from a molecular understanding of the dynamics in KRAS and NRAS and their oncogenic mutants. Here we characterize switch-1 dynamics in GTP-state KRAS and NRAS by 31P NMR, by 15N relaxation dispersion NMR, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations. In GMPPNP-bound KRAS and NRAS, we see the co-existence of two conformational states, corresponding to an "inactive" state-1 and an "active" state-2, as previously reported. The KRAS oncogenic mutations G12D, G12C and G12V only slightly affect this equilibrium towards the "inactive" state-1, with rank order wt < G12C < G12D < G12V. In contrast, the NRAS Q61R oncogenic mutation shifts the equilibrium fully towards the "active" state-2. Our molecular dynamics simulations explain this by the observation of a transient hydrogen bond between the Arg61 side chain and the Thr35 backbone carbonyl oxygen. NMR relaxation dispersion experiments with GTP-bound KRAS Q61R confirm a drastic decrease in the population of state-1, but still detect a small residual population (1.8%) of this conformer. HDX-MS indicates that higher populations of state-1 correspond to increased hydrogen-deuterium exchange rates in some regions and increased flexibility, whereas low state-1 populations are associated with KRAS rigidification. We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network. (This journal is © The Royal Society of Chemistry.) |
| Competing Interests: | There are no conflicts to declare. |
| Σχόλια: | Erratum in: RSC Chem Biol. 2026 May 5. doi: 10.1039/d6cb90018f.. (PMID: 42094779) |
| Entry Date(s): | Date Created: 20241212 Latest Revision: 20260507 |
| Update Code: | 20260507 |
| PubMed Central ID: | PMC11629925 |
| DOI: | 10.1039/d4cb00233d |
| PMID: | 39664928 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 2633-0679 |
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| DOI: | 10.1039/d4cb00233d |