6GOE

KRAS full length G12V GPPNHP

6GOE の概要

• エントリーDOI: 10.2210/pdb6goe/pdb
• 関連するPDBエントリー: 6GOD
• 分子名称: GTPase KRas, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (4 entities in total)
• 機能のキーワード: kras full lenght, oncoprotein
• 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: 20091.55

構造登録者

Cruz-Migoni, A.,Quevedo, C.E.,Carr, S.B.,Ehebauer, M.T.,Phillips, S.V.E.,Rabbitts, T.H. (登録日: 2018-06-01, 公開日: 2019-02-06, 最終更新日: 2024-01-17)

主引用文献

Cruz-Migoni, A.,Canning, P.,Quevedo, C.E.,Bataille, C.J.R.,Bery, N.,Miller, A.,Russell, A.J.,Phillips, S.E.V.,Carr, S.B.,Rabbitts, T.H.
Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds.
Proc. Natl. Acad. Sci. U.S.A., 116:2545-2550, 2019

PubMed Abstract: The gene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein-protein interactions. We have refined crystallization conditions for KRAS-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein-protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein-protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein-protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.

PubMed: 30683716
DOI: 10.1073/pnas.1811360116

実験手法

X-RAY DIFFRACTION (1.6 Å)