7KFZ

Structure of a ternary KRas(G13D)-SOS complex

Summary for 7KFZ

• Entry DOI: 10.2210/pdb7kfz/pdb
• EMDB information: 22857
• Descriptor: GTPase KRas, Son of sevenless homolog 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (4 entities in total)
• Functional Keywords: ras, sos, gtpase, hydrolase-signaling protein complex, hydrolase/signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 96769.89

Authors

Liu, C.,Moghadamchargari, Z.,Laganowsky, A.,Zhao, M. (deposition date: 2020-10-15, release date: 2021-03-31, Last modification date: 2024-03-06)

Primary citation

Moghadamchargari, Z.,Shirzadeh, M.,Liu, C.,Schrecke, S.,Packianathan, C.,Russell, D.H.,Zhao, M.,Laganowsky, A.
Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also allosterically modulated by an active Ras (Ras-GTP). However, it remains poorly understood how oncogenic Ras mutants interact with SOS and modulate its activity. Here, native ion mobility-mass spectrometry is employed to monitor the assembly of the catalytic domain of SOS (SOS) with KRas and three cancer-associated mutants (G12C, G13D, and Q61H), leading to the discovery of different molecular assemblies and distinct conformers of SOS engaging KRas. We also find KRas exhibits high affinity for SOS and is a potent allosteric modulator of its activity. A structure of the KRas•SOS complex was determined using cryogenic electron microscopy providing insight into the enhanced affinity of the mutant protein. In addition, we find that KRas-GTP can allosterically increase the nucleotide exchange rate of KRas at the active site more than twofold compared to KRas-GTP. Furthermore, small-molecule Ras•SOS disruptors fail to dissociate KRas•SOS complexes, underscoring the need for more potent disruptors. Taken together, a better understanding of the interaction between oncogenic Ras mutants and SOS will provide avenues for improved therapeutic interventions.

PubMed: 33723061
DOI: 10.1073/pnas.2022403118

Experimental method

ELECTRON MICROSCOPY (3.47 Å)