8TVK

KRAS 1-169 G12C Mutant at 100k

Summary for 8TVK

• Entry DOI: 10.2210/pdb8tvk/pdb
• Descriptor: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: gtpase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 19785.36

Authors

Deck, S.L.,Xu, M.,Milano, S.K.,Aplin, C. (deposition date: 2023-08-18, release date: 2024-08-28, Last modification date: 2025-03-26)

Primary citation

Deck, S.L.,Xu, M.,Milano, S.K.,Cerione, R.A.
Revealing Functional Hotspots: Temperature-Dependent Crystallography of K-RAS Highlights Allosteric and Druggable Sites.
Biorxiv, 2025

PubMed Abstract: K-RAS mutations drive oncogenesis in multiple cancers, yet the lack of druggable sites has long hindered therapeutic development. Here, we use multi-temperature X-ray crystallography (MT-XRC) to capture functionally relevant K-RAS conformations across a temperature gradient, spanning cryogenic to physiological and even "fever" conditions, and show how cryogenic conditions may obscure key dynamic states as targets for new drug development. This approach revealed a temperature-dependent conformational landscape of K-RAS, shedding light on the dynamic nature of key regions. We identified significant conformational changes occurring at critical sites, including known allosteric and drug-binding pockets, which were hidden under cryogenic conditions but later discovered to be critically important for drug-protein interactions and inhibitor design. These structural changes align with regions previously highlighted by large-scale mutational studies as functionally significant. However, our MT-XRC analysis provides precise structural snapshots, capturing the exact conformations of these potentially important allosteric sites in unprecedented detail. Our findings underscore the necessity of advancing tools like MT-XRC to visualize conformational transitions that may be important in signal propagation which are missed by standard cryogenic XRC and to address hard-to-drug targets through rational drug design. This approach not only provides unique structural insights into K-RAS signaling events and identifies new potential sites to target with drug candidates but also establishes a powerful framework for discovering therapeutic opportunities against other challenging drug targets.

PubMed: 40060414
DOI: 10.1101/2025.02.27.639303

Experimental method

X-RAY DIFFRACTION (1.04 Å)