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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength)	RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site Katarzyna Z. Haza , Heather L. Martin , Ajinkya Rao , Amy L. Turner , Sophie E. Saunders , Britta Petersen , Christian Tiede , Kevin Tipping , Anna A. Tang , Modupe Ajayi , Thomas Taylor , Maia Harvey , Keri M. Fishwick , Thomas L. Adams , Thembaninkosi G. Gaule , Chi H. Trinh , Matthew Johnson , Alexander L. Breeze , Thomas A. Edwards , Michael J. Mcpherson , Darren C. Tomlinson Nature Communications 12 DOI: 10.1038/s41467-021-24316-0 Diamond Proposal Number(s): [19248] Open Access Show Abstract ▼ 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.	Jun 2021

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