5L6J

Uba1 in complex with Ub-MLN7243 covalent adduct

Summary for 5L6J

• Entry DOI: 10.2210/pdb5l6j/pdb
• Descriptor: Ubiquitin-activating enzyme E1 1, Ubiquitin-40S ribosomal protein S31, SULFATE ION, ... (7 entities in total)
• Functional Keywords: e1 enzyme, ubiquitin activation, uba1 inhibitor, adenosyl sulfamate, ligase
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Cellular location: Cytoplasm: P22515; Ubiquitin: Cytoplasm . 40S ribosomal protein S31: Cytoplasm : P05759
• Total number of polymer chains: 4
• Total formula weight: 248867.77

Authors

Misra, M.,Schindelin, H. (deposition date: 2016-05-30, release date: 2017-06-14, Last modification date: 2025-01-29)

Primary citation

Misra, M.,Kuhn, M.,Lobel, M.,An, H.,Statsyuk, A.V.,Sotriffer, C.,Schindelin, H.
Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme.
Structure, 25:1120-1129.e3, 2017

PubMed Abstract: Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site. When compared with the previously reported structures of various E1 enzymes, our structures provide the basis of the preferences of these inhibitors for different Ub/Ubl-activating enzymes. In vitro inhibition assays and molecular dynamics simulations validated the specificities of the inhibitors as deduced from the structures. Taken together, the structures establish a framework for the development of additional compounds targeting E1 enzymes, which will display higher potency and selectivity.

PubMed: 28578874
DOI: 10.1016/j.str.2017.05.001

Experimental method

X-RAY DIFFRACTION (2.68 Å)