6YR8
Affimer K6 - KRAS protein complex
Summary for 6YR8
| Entry DOI | 10.2210/pdb6yr8/pdb |
| Descriptor | GTPase KRas, Affimer K6, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total) |
| Functional Keywords | protein complex, affimer, kras, inhibitor, protein binding |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 32254.57 |
| Authors | Trinh, C.H.,Haza, K.Z.,Rao, A.,Martin, H.L.,Tiede, C.,Edwards, T.A.,McPherson, M.J.,Tomlinson, D.C. (deposition date: 2020-04-19, release date: 2020-07-08, Last modification date: 2024-01-24) |
| Primary citation | Haza, K.Z.,Martin, H.L.,Rao, A.,Turner, A.L.,Saunders, S.E.,Petersen, B.,Tiede, C.,Tipping, K.,Tang, A.A.,Ajayi, M.,Taylor, T.,Harvey, M.,Fishwick, K.M.,Adams, T.L.,Gaule, T.G.,Trinh, C.H.,Johnson, M.,Breeze, A.L.,Edwards, T.A.,McPherson, M.J.,Tomlinson, D.C. RAS-inhibiting biologics identify and probe druggable pockets including an SII-alpha 3 allosteric site. Nat Commun, 12:4045-4045, 2021 Cited by PubMed 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. PubMed: 34193876DOI: 10.1038/s41467-021-24316-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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