6MS9

GDP-bound KRAS P34R mutant

6MS9 の概要

• エントリーDOI: 10.2210/pdb6ms9/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: gtpase kras hydrolysis, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 59193.49

構造登録者

Bera, A.K.,Westover, K.D. (登録日: 2018-10-16, 公開日: 2020-04-15, 最終更新日: 2023-10-11)

主引用文献

Bera, A.K.,Lu, J.,Lu, C.,Li, L.,Gondi, S.,Yan, W.,Nelson, A.,Zhang, G.,Westover, K.D.
GTP hydrolysis is modulated by Arg34 in the RASopathy-associated KRASP34R.
Birth Defects Res, 112:708-717, 2020

PubMed Abstract: RAS proteins are commonly mutated in cancerous tumors, but germline RAS mutations are also found in RASopathy syndromes such as Noonan syndrome (NS) and cardiofaciocutaneous (CFC) syndrome. Activating RAS mutations can be subclassified based on their activating mechanisms. Understanding the structural basis for these mechanisms may provide clues for how to manage associated health conditions. We determined high-resolution X-ray structures of the RASopathy mutant KRAS seen in NS and CFCS. GTP and GDP-bound KRAS crystallized in multiple forms, with each lattice consisting of multiple protein conformations. In all GTP-bound conformations, the switch regions are not compatible with GAP binding, suggesting a structural mechanism for the GAP insensitivity of this RAS mutant. However, GTP-bound conformations are compatible with intrinsic nucleotide hydrolysis, including one that places R34 in a position analogous to the GAP arginine finger or intrinsic arginine finger found in heterotrimeric G proteins, which may support intrinsic GTP hydrolysis. We also note that the affinity between KRAS and RAF-RBD is decreased, suggesting another possible mechanism for dampening of RAS signaling. These results may provide a foothold for development of new mutation-specific strategies to address KRAS -driven diseases.

PubMed: 32187889
DOI: 10.1002/bdr2.1647

実験手法

X-RAY DIFFRACTION (1.49 Å)