Year: 2021
Type: article
Abstract: Significance Disrupting the interaction between Ras and SOS has emerged as an attractive therapeutic strategy. Here, we characterized the assembly of the catalytic domain of SOS (SOS cat ) with oncogenic KRas mutants using native mass spectrometry. By resolving distinct molecular species, we show KRas mutants engage SOS cat differently and the G13D KRas mutant robustly engages SOS cat . A structure of KRas G13D in complex with SOS cat shows repositioning of switch I and II regions within KRas G13D . Moreover, potent small-molecule Ras•SOS disruptors do not dissociate KRas G13D •SOS cat complexes when KRas G13D –GTP is bound at allosteric site of SOS cat . These results underscore the need for more potent Ras•SOS disruptors when considering targeting the disruption of different oncogenic Ras mutants in complex with SOS.
Institutions: Texas A&M University, University of Chicago
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: Native ion mobility mass spectrometry studies of potassium inward rectifier channels: insight into gating and lipid binding, G4582736256, G7229056886, Development of high resolution mobility measurements for structural biology, NCCAT: National Center for CryoEM Access and Training, Resource for Native Mass Spectrometry Guided Structural Biology
OpenAlex ID: W3137876780