6xoh

Structure of SUMO1-ML00789344 adduct bound to SAE

spinqualitylabelsall models 6xoh, resolution 2.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6xoh is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.226Å Ligands: SO4, VB7, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SAE1_HUMAN The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2. Publication Abstract from PubMed 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. Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.,Langston SP, Grossman S, England D, Afroze R, Bence N, Bowman D, Bump N, Chau R, Chuang BC, 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 MS, Lane SW, 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 MD, Song K, Soucy T, Wang Y, Xu H, Yang X, Zawadzka A, Zhang J, Pulukuri SM J Med Chem. 2021 Mar 11;64(5):2501-2520. doi: 10.1021/acs.jmedchem.0c01491. Epub , 2021 Feb 25. PMID:33631934 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also SUMO 3D Structures

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