Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants
Zahra Moghadamchargari, Mehdi Shirzadeh, Chang Liu, Samantha Schrecke, Charles Packianathan, David H. Russell, Minglei Zhao, Arthur Laganowsky
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.