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Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities.
Wang, Hui; Liu, Dan; Yu, Yongkui; Fang, Mengqi; Gu, Xue; Long, Dong.
Afiliación
  • Wang H; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
  • Liu D; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
  • Yu Y; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
  • Fang M; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
  • Gu X; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
  • Long D; MOE Key Laboratory for Cellular Dynamics and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China. dlong@ustc.edu.cn.
Phys Chem Chem Phys ; 25(2): 1045-1053, 2023 Jan 04.
Article en En | MEDLINE | ID: mdl-36537570
Recent advances in direct inhibition of Ras benefit from the protein's intrinsic dynamic nature that derives therapeutically vulnerable conformers bearing transiently formed cryptic pockets. Hotspot mutants of Ras are major tumor drivers and are hyperactivated in cells at variable levels, which may require allele-specific strategies for effective targeting. However, it remains unclear how the prevalent oncogenic mutations and activation states perturb the free energy landscape governing the protein dynamics and druggability. Here we characterized the nucleotide state- and allele-dependent alterations of Ras conformational dynamics using a combined NMR experimental and computational approach and constructed quantitative ensembles revealing the conservation of the cryptic SI/II-P and SII-P pockets in different states and alleles. Highly local but critical conformational reorganizations that undermine the SII-P accessibility to residue 12 have been identified as a common mechanism resulting in the low reactivities of Ras·GTP as well as Ras(G12D)·GDP with covalent SII-P inhibitors. Our results strongly support the conformational selection scenario for interactions between Ras and the previously reported binders and offer insights for the future development of state- and allele-specific, as well as pan-Ras, inhibitors.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Nucleótidos Tipo de estudio: Prognostic_studies Idioma: En Revista: Phys Chem Chem Phys Asunto de la revista: BIOFISICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Nucleótidos Tipo de estudio: Prognostic_studies Idioma: En Revista: Phys Chem Chem Phys Asunto de la revista: BIOFISICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: China