5USJ

Crystal Structure of human KRAS G12D mutant in complex with GDPNP

5USJ の概要

• エントリーDOI: 10.2210/pdb5usj/pdb
• 関連するPDBエントリー: 5UQW 5US4
• 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, gtpase, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 132285.99

構造登録者

Huang, C.S.,Kaplan, A.,Stockwell, B.R.,Tong, L. (登録日: 2017-02-13, 公開日: 2017-03-22, 最終更新日: 2024-03-06)

主引用文献

Welsch, M.E.,Kaplan, A.,Chambers, J.M.,Stokes, M.E.,Bos, P.H.,Zask, A.,Zhang, Y.,Sanchez-Martin, M.,Badgley, M.A.,Huang, C.S.,Tran, T.H.,Akkiraju, H.,Brown, L.M.,Nandakumar, R.,Cremers, S.,Yang, W.S.,Tong, L.,Olive, K.P.,Ferrando, A.,Stockwell, B.R.
Multivalent Small-Molecule Pan-RAS Inhibitors.
Cell, 168:878-889.e29, 2017

PubMed Abstract: Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.

PubMed: 28235199
DOI: 10.1016/j.cell.2017.02.006

実験手法

X-RAY DIFFRACTION (1.94 Å)