9Y1W

Crystal structure of NRas-G12D in complex with GDP and compound 27

これはPDB形式変換不可エントリーです。

9Y1W の概要

• エントリーDOI: 10.2210/pdb9y1w/pdb
• 関連するPDBエントリー: 9Y0G
• 分子名称: GTPase NRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: inhibitor, gtpase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40959.18

構造登録者

Johnson, T.A.,Cross, J.B. (登録日: 2025-08-31, 公開日: 2026-02-25, 最終更新日: 2026-03-04)

主引用文献

Cox, J.B.,Nair, V.,Mandal, P.,Reyna, N.,Tran, T.,Mustachio, L.M.,Bardenhagen, J.,Fawver, J.,Shepard, H.,Hickey, A.M.,Wu, Q.,Rodriguez, C.,Yu, F.,Phan, P.,Mendiola, A.J.,Johnson, R.,Thapar, R.,Johnson, T.,Jiang, Y.,Cross, J.B.,Do, M.K.G.,Jones, P.,Marsalek, J.,Heffernan, T.,Soth, M.J.,Nagy, E.
Structure-Guided Development of NRAS G12D Inhibitors Based on a 5‐Azaindole Core.
Acs Med.Chem.Lett., 17:425-432, 2026

PubMed Abstract: NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a tool compound for further studies of NRAS biology. The development process revealed key insights into gaining selectivity between NRAS and KRAS proteins. Notably, stabilization of the p-loop and substitution toward Leu 95 while maintaining key interactions with Asp12, Gly60, and Asp69 improved NRAS G12D potency and resulted in selectivity against wild-type KRAS/non-responder.

PubMed: 41704364
DOI: 10.1021/acsmedchemlett.5c00647

実験手法

X-RAY DIFFRACTION (1.95 Å)