6YR8

Affimer K6 - KRAS protein complex

6YR8 の概要

• エントリーDOI: 10.2210/pdb6yr8/pdb
• 分子名称: GTPase KRas, Affimer K6, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: protein complex, affimer, kras, inhibitor, protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32254.57

構造登録者

Trinh, C.H.,Haza, K.Z.,Rao, A.,Martin, H.L.,Tiede, C.,Edwards, T.A.,McPherson, M.J.,Tomlinson, D.C. (登録日: 2020-04-19, 公開日: 2020-07-08, 最終更新日: 2024-01-24)

主引用文献

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

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: 34193876
DOI: 10.1038/s41467-021-24316-0

実験手法

X-RAY DIFFRACTION (1.9 Å)