9GLU

Crystal structure of KRasG12D-GDP in complex with the peptide MPB1

9GLU の概要

• エントリーDOI: 10.2210/pdb9glu/pdb
• 分子名称: Isoform 2B of GTPase KRas, Peptide MPB1, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: gtpase, signaling protein, small g-protein, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 42968.55

構造登録者

Ostermann, N.,Zink, F. (登録日: 2024-08-28, 公開日: 2025-12-10)

主引用文献

Beyer, K.S.,Klein, J.,Katz, S.,Welker, P.,Lanter, M.,Guthy, D.,Pollehn, K.,Gluck-Gade, A.,Bleu, M.,Desogus, J.,Hattenberger, M.,Borrello, D.,Abdul Rahman, W.,Zink, F.,Ostermann, N.,Jahnke, W.,Dumelin, C.E.,Leder, L.,Esser, O.,Muller, L.,Marzinzik, A.,Cebe, R.,Muller, K.,Galli, G.G.,Tordella, L.,Cotesta, S.,Brachmann, S.M.,Maira, S.M.
Identification and characterization of binders to a cryptic and functional pocket in KRAS.
Nat Commun, 16:10836-10836, 2025

PubMed Abstract: RAS proteins control cell proliferation and activating mutations are collectively the most frequent oncogenic event observed in cancer patients, justifying investments into multiple drug discovery efforts. While RAS-directed therapeutic agents targeting either the inactive GDP-bound or the active GTP-bound state have entered the clinic, invariably resistance is observed. Mutations at drug binding sites represent a common resistance mechanism indicating the need to discover new targetable pockets in RAS. Such efforts are hindered by the small globular size of the protein, for long considered undruggable. Here we perform macrocyclic peptides mRNA and nanobody yeast display screens and discover a targetable ligand-induced pocket in RAS. In vitro and cellular experiments with the KM12 and KM12-AM nanobodies show RAS inhibition via displacement of cRAF, by affecting their protein-protein interaction via the less studied cRAF CRD domain. Further, we provide orthogonal functional validation for the discovered binding pocket via mutagenesis experiments. Notably, the discovered RAS-targeting approach enables simultaneous targeting of both GTP-bound active and GDP-bound inactive states and leaves the SwII pocket unaltered, opening possibilities of combinatorial approaches with clinically approved SwII pocket inhibitors.

PubMed: 41330964
DOI: 10.1038/s41467-025-65844-3

実験手法

X-RAY DIFFRACTION (1.9 Å)