6XOH

Structure of SUMO1-ML00789344 adduct bound to SAE

6XOH の概要

• エントリーDOI: 10.2210/pdb6xoh/pdb
• 関連するPDBエントリー: 6XOG
• 分子名称: SUMO-activating enzyme subunit 1, SUMO-activating enzyme subunit 2, Small ubiquitin-related modifier 1, ... (7 entities in total)
• 機能のキーワード: sae, sumo1, covalent inhibitor, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 122081.39

構造登録者

Sintchak, M.,Lane, W.,Bump, N. (登録日: 2020-07-07, 公開日: 2021-03-24, 最終更新日: 2024-11-20)

主引用文献

Langston, S.P.,Grossman, S.,England, D.,Afroze, R.,Bence, N.,Bowman, D.,Bump, N.,Chau, R.,Chuang, B.C.,Claiborne, C.,Cohen, L.,Connolly, K.,Duffey, M.,Durvasula, N.,Freeze, S.,Gallery, M.,Galvin, K.,Gaulin, J.,Gershman, R.,Greenspan, P.,Grieves, J.,Guo, J.,Gulavita, N.,Hailu, S.,He, X.,Hoar, K.,Hu, Y.,Hu, Z.,Ito, M.,Kim, M.S.,Lane, S.W.,Lok, D.,Lublinsky, A.,Mallender, W.,McIntyre, C.,Minissale, J.,Mizutani, H.,Mizutani, M.,Molchinova, N.,Ono, K.,Patil, A.,Qian, M.,Riceberg, J.,Shindi, V.,Sintchak, M.D.,Song, K.,Soucy, T.,Wang, Y.,Xu, H.,Yang, X.,Zawadzka, A.,Zhang, J.,Pulukuri, S.M.
Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.
J.Med.Chem., 64:2501-2520, 2021

PubMed Abstract: SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

PubMed: 33631934
DOI: 10.1021/acs.jmedchem.0c01491

実験手法

X-RAY DIFFRACTION (2.226 Å)