6XOG

Structure of SUMO1-ML786519 adduct bound to SAE

Summary for 6XOG

• Entry DOI: 10.2210/pdb6xog/pdb
• Descriptor: SUMO-activating enzyme subunit 1, SUMO-activating enzyme subunit 2, Small ubiquitin-related modifier 1, ... (7 entities in total)
• Functional Keywords: sae, sumo1, covalent inhibitor, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 122165.26

Authors

Sintchak, M.,Lane, W.,Bump, N. (deposition date: 2020-07-07, release date: 2021-03-10, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.98 Å)