7KMR

Crystal structure analysis of human KRAS mutant

7KMR の概要

• エントリーDOI: 10.2210/pdb7kmr/pdb
• 分子名称: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE (3 entities in total)
• 機能のキーワード: hydrolase, gtpase, oncogenic
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24146.99

構造登録者

Seo, H.-S.,Dhe-Paganon, S. (登録日: 2020-11-03, 公開日: 2021-11-10, 最終更新日: 2023-10-18)

主引用文献

Johnson, C.W.,Seo, H.S.,Terrell, E.M.,Yang, M.H.,KleinJan, F.,Gebregiworgis, T.,Gasmi-Seabrook, G.M.C.,Geffken, E.A.,Lakhani, J.,Song, K.,Bashyal, P.,Popow, O.,Paulo, J.A.,Liu, A.,Mattos, C.,Marshall, C.B.,Ikura, M.,Morrison, D.K.,Dhe-Paganon, S.,Haigis, K.M.
Regulation of GTPase function by autophosphorylation.
Mol.Cell, 82:950-968.e14, 2022

PubMed Abstract: A unifying feature of the RAS superfamily is a conserved GTPase cycle by which these proteins transition between active and inactive states. We demonstrate that autophosphorylation of some GTPases is an intrinsic regulatory mechanism that reduces nucleotide hydrolysis and enhances nucleotide exchange, altering the on/off switch that forms the basis for their signaling functions. Using X-ray crystallography, nuclear magnetic resonance spectroscopy, binding assays, and molecular dynamics on autophosphorylated mutants of H-RAS and K-RAS, we show that phosphoryl transfer from GTP requires dynamic movement of the switch II region and that autophosphorylation promotes nucleotide exchange by opening the active site and extracting the stabilizing Mg. Finally, we demonstrate that autophosphorylated K-RAS exhibits altered effector interactions, including a reduced affinity for RAF proteins in mammalian cells. Thus, autophosphorylation leads to altered active site dynamics and effector interaction properties, creating a pool of GTPases that are functionally distinct from their non-phosphorylated counterparts.

PubMed: 35202574
DOI: 10.1016/j.molcel.2022.02.011

実験手法

X-RAY DIFFRACTION (1.51 Å)