9C41

Crystal structure of GDP-bound KRAS G12D/E62Q: Suppressing G12D oncogenicity via second-site E62Q mutation

9C41 の概要

• エントリーDOI: 10.2210/pdb9c41/pdb
• 分子名称: Isoform 2B of GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: kras, ras, nucleotide-binding protein, signaling protein, g12d, e62q, oncoprotein
• 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: 39802.80

構造登録者

Tran, T.H.,Dharmaiah, S.,Simanshu, D.K. (登録日: 2024-06-02, 公開日: 2025-10-08)

主引用文献

Kwon, J.J.,Dilly, J.,Liu, S.,Kim, E.,Bian, Y.,Dharmaiah, S.,Tran, T.H.,Kapner, K.S.,Ly, S.H.,Yang, X.,Rabara, D.,Waybright, T.J.,Giacomelli, A.O.,Hong, A.L.,Misek, S.,Wang, B.,Ravi, A.,Doench, J.G.,Beroukhim, R.,Lemke, C.T.,Haigis, K.M.,Esposito, D.,Root, D.E.,Nissley, D.V.,Stephen, A.G.,McCormick, F.,Simanshu, D.K.,Hahn, W.C.,Aguirre, A.J.
Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity.
Biorxiv, 2024

PubMed Abstract: To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRAS mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRAS second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.

PubMed: 39484452
DOI: 10.1101/2024.10.22.618529

実験手法

X-RAY DIFFRACTION (1.94 Å)