5WPM

KRas G12V, bound to GppNHp and miniprotein 225-11(A30R)

5WPM の概要

• エントリーDOI: 10.2210/pdb5wpm/pdb
• 分子名称: GTPase KRas, Ras binding peptide, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (6 entities in total)
• 機能のキーワード: inhibitor, complex, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 27357.89

構造登録者

Lee, S.-J.,Shim, S.Y.,McGee, J.H.,Verdine, G.L. (登録日: 2017-08-05, 公開日: 2018-01-03, 最終更新日: 2024-10-23)

主引用文献

McGee, J.H.,Shim, S.Y.,Lee, S.J.,Swanson, P.K.,Jiang, S.Y.,Durney, M.A.,Verdine, G.L.
Exceptionally high-affinity Ras binders that remodel its effector domain.
J. Biol. Chem., 293:3265-3280, 2018

PubMed Abstract: The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule-binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naïve library and their evolution to afford versions with midpicomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands. We also report a Ras point mutant that stabilizes the protein in the open conformation trapped by these miniproteins. These findings provide new tools for studying Ras structure and function and present opportunities for the development of both miniprotein and small-molecule inhibitors that directly target the Ras proteins.

PubMed: 29282294
DOI: 10.1074/jbc.M117.816348

実験手法

X-RAY DIFFRACTION (1.72 Å)