Journal article
Delineating the RAS Conformational Landscape
Cancer research (Chicago, Ill.), v 82(13), pp 2485-2498
01 Jul 2022
PMID: 35536216
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Mutations in RAS isoforms (KRAS, NRAS, and HRAS) are among the most frequent oncogenic alterations in many cancers, making these proteins high priority therapeutic targets. Effectively targeting RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structural catalog of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. Here we present an expanded classification of RAS conformations based on analyses of the catalytic switch 1 (SW1) and switch 2 (SW2) loops. From 721 human KRAS, NRAS, and HRAS structures available in the Protein Data Bank (206 RAS-protein cocomplexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of Y32 in SW1 and Y71 in SW2. Clustering all well-modeled SW1 and SW2 loops using a density-based machine learning algorithm defined additional conformational subsets, some previously undescribed. Three SW1 conformations and nine SW2 conformations were identified, each associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation could be further subdivided on the basis of the hydrogen bond type made between Y32 and the GTP y-phosphate. Further analysis clarified the catalytic impact of G12D and G12V mutations and the inhibitor chemistries that bind to each druggable RAS conformation. Overall, this study has expanded our understanding of RAS structural biology, which could facilitate future RAS drug discovery. Significance: Analysis of > 700 RAS structures helps define an expanded landscape of active, inactive, and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS inhibitor-binding modes.
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Details
- Title
- Delineating the RAS Conformational Landscape
- Creators
- Mitchell I. Parker - Drexel UniversityJoshua E. Meyer - Fox Chase Cancer CenterErica A. Golemis - Fox Chase Cancer CenterRoland L. Dunbrack Jr - Fox Chase Canc Ctr, Program Mol Therapeut, Philadelphia, PA USA
- Publication Details
- Cancer research (Chicago, Ill.), v 82(13), pp 2485-2498
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 14
- Grant note
- F30 GM142263; R35 GM122517 / NIH NIGMS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) P30 CA006927 / NIH NCI Core Grant Colon Cancer Alliance Funding
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine
- Web of Science ID
- WOS:000831492000001
- Scopus ID
- 2-s2.0-85134084094
- Other Identifier
- 991020099738204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology