36OL

Crystal Structure of KRAS WT complexed with GMPPNP

36OL の概要

• エントリーDOI: 10.2210/pdb36ol/pdb
• 分子名称: GTPase KRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, small gtpase, cancer, tri-complex, signaling protein-inhibitor complex, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39872.74

構造登録者

Tomlinson, A.C.A.,Knox, J.E.,Yano, J.K. (登録日: 2026-06-23, 公開日: 2026-07-01)

主引用文献

Seamon, K.J.,Zhuang, Y.,Yang, Y.C.,Chakraborty, S.,Cregg, J.,Tomlinson, A.C.A.,Gould, A.,Ahler, E.,Maldonato, B.J.,Spradlin, J.N.,Pota, K.,Weller, C.,Marquez, A.,Wang, Z.,Koltun, E.S.,Knox, J.E.,Gill, A.L.,Smith, J.A.M.,Singh, M.,Jiang, J.,Wildes, D.,Holderfield, M.
Selective Inhibition of KRASG13C Reveals an Increased Dependence on Wild-Type RAS Isoforms in Codon 13 RAS-Mutant Cancers.
Cancer Discov, 2026

PubMed Abstract: Covalent KRAS G12C inhibitors have changed the treatment landscape for NSCLC and CRC patients, but numerous RAS-mutant cancers lack approved targeted therapies. Here we describe RMC-8839, an oral RAS(ON) G13C-selective, covalent, tri-complex inhibitor that induced tumor regressions in selected KRAS G13C-mutant xenograft models. However, one-third of KRAS G13C-mutant human cancer cell lines in vitro showed incomplete RAS pathway suppression despite near-complete KRAS G13C engagement, suggesting a role for wild-type RAS(ON). We find that codon 13-mutant RAS differs from other KRAS mutations, exhibiting decreased stability, increased nucleotide exchange, and substantial intrinsic and GAP-stimulated GTP hydrolysis, which decreases oncogenicity. Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.

PubMed: 42329095
DOI: 10.1158/2159-8290.CD-25-0886

実験手法

X-RAY DIFFRACTION (2.05 Å)