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RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site

DOI: 10.1038/s41467-021-24316-0 DOI Help

Authors: Katarzyna Z. Haza (University of Leeds) , Heather L. Martin (University of Leeds) , Ajinkya Rao (University of Leeds) , Amy L. Turner (University of Leeds) , Sophie E. Saunders (University of Leeds) , Britta Petersen (University of Leeds) , Christian Tiede (University of Leeds) , Kevin Tipping (University of Leeds) , Anna A. Tang (University of Leeds) , Modupe Ajayi (University of Leeds) , Thomas Taylor (University of Leeds) , Maia Harvey (University of Leeds) , Keri M. Fishwick (University of Leeds) , Thomas L. Adams (University of Leeds) , Thembaninkosi G. Gaule (University of Leeds) , Chi H. Trinh (Institute of Molecular and Cellular Biology, University of Leeds) , Matthew Johnson (Avacta Life Sciences) , Alexander L. Breeze (University of Leeds) , Thomas A. Edwards (University of Leeds) , Michael J. Mcpherson (University of Leeds) , Darren C. Tomlinson (University of Leeds)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 19248

Open Access Open Access

Abstract: RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID30A-1 at ESRF

Added On: 21/07/2021 10:30


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)