5UM6

Crystal Structure of S. pombe Uba1 in a closed conformation

Summary for 5UM6

• Entry DOI: 10.2210/pdb5um6/pdb
• Descriptor: Ubiquitin-activating enzyme E1 1, SULFATE ION, N-(2-{[(4-chlorophenyl)methyl]disulfanyl}ethyl)decan-1-amine, ... (4 entities in total)
• Functional Keywords: rossmann-like fold, ubiquitin-like fold, ubiquitin activating enzyme, atp binding, ligase activity, atp/mg binding, ubiquitin e2 binding, ligase, transferase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Schizosaccharomyces pombe (strain 972 / ATCC 24843) (Fission yeast)
• Total number of polymer chains: 1
• Total formula weight: 112332.43

Authors

Lv, Z.,Yuan, L.,Aldana-Masangkay, G.,Atkison, J.H.,Chen, Y.,Olsen, S.K. (deposition date: 2017-01-26, release date: 2017-06-14, Last modification date: 2024-10-23)

Primary citation

Lv, Z.,Yuan, L.,Atkison, J.H.,Aldana-Masangkay, G.,Chen, Y.,Olsen, S.K.
Domain alternation and active site remodeling are conserved structural features of ubiquitin E1.
J. Biol. Chem., 292:12089-12099, 2017

PubMed Abstract: E1 enzymes for ubiquitin (Ub) and Ub-like modifiers (Ubls) harbor two catalytic activities that are required for Ub/Ubl activation: adenylation and thioester bond formation. Structural studies of the E1 for the Ubl mall biquitin-like difier (SUMO) revealed a single active site that is transformed by a conformational switch that toggles its competency for catalysis of these two distinct chemical reactions. Although the mechanisms of adenylation and thioester bond formation revealed by SUMO E1 structures are thought to be conserved in Ub E1, there is currently a lack of structural data supporting this hypothesis. Here, we present a structure of Uba1 in which the second catalytic cysteine half-domain (SCCH domain) harboring the catalytic cysteine has undergone a 106° rotation that results in a completely different network of intramolecular interactions between the SCCH and adenylation domains and translocation of the catalytic cysteine 12 Å closer to the Ub C terminus compared with previous Uba1 structures. SCCH domain alternation is accompanied by conformational changes within the Uba1 adenylation domains that effectively disassemble the adenylation active site. Importantly, the structural and biochemical data suggest that domain alternation and remodeling of the adenylation active site are interconnected and are intrinsic structural features of Uba1 and that the overall structural basis for adenylation and thioester bond formation exhibited by SUMO E1 is indeed conserved in Ub E1. Finally, the mechanistic insights provided by the novel conformational snapshot of Uba1 presented in this study may guide efforts to develop small molecule inhibitors of this critically important enzyme that is an active target for anticancer therapeutics.

PubMed: 28572513
DOI: 10.1074/jbc.M117.787622

Experimental method

X-RAY DIFFRACTION (2.794 Å)