3qht

Crystal Structure of the Monobody ySMB-1 bound to yeast SUMO

spinqualitylabelsall models 3qht, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3qht is a 4 chain structure with sequence from Atcc 18824 and Synthetic construct sequences. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Gene: SMT3, YDR510W, D9719.15 (ATCC 18824) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [SMT3_YEAST] Not known; suppressor of MIF2 mutations. Publication Abstract from PubMed Discriminating closely related molecules remains a major challenge in the engineering of binding proteins and inhibitors. Here we report the development of highly selective inhibitors of small ubiquitin-related modifier (SUMO) family proteins. SUMOylation is involved in the regulation of diverse cellular processes. Functional differences between two major SUMO isoforms in humans, SUMO1 and SUMO2/3, are thought to arise from distinct interactions mediated by each isoform with other proteins containing SUMO-interacting motifs (SIMs). However, the roles of such isoform-specific interactions are largely uncharacterized due in part to the difficulty in generating high-affinity, isoform-specific inhibitors of SUMO/SIM interactions. We first determined the crystal structure of a "monobody," a designed binding protein based on the fibronectin type III scaffold, bound to the yeast homolog of SUMO. This structure illustrated a mechanism by which monobodies bind to the highly conserved SIM-binding site while discriminating individual SUMO isoforms. Based on this structure, we designed a SUMO-targeted library from which we obtained monobodies that bound to the SIM-binding site of human SUMO1 with K(d) values of approximately 100 nM but bound to SUMO2 400 times more weakly. The monobodies inhibited SUMO1/SIM interactions and, unexpectedly, also inhibited SUMO1 conjugation. These high-affinity and isoform-specific inhibitors will enhance mechanistic and cellular investigations of SUMO biology. Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design.,Gilbreth RN, Truong K, Madu I, Koide A, Wojcik JB, Li NS, Piccirilli JA, Chen Y, Koide S Proc Natl Acad Sci U S A. 2011 May 10;108(19):7751-6. Epub 2011 Apr 25. PMID:21518904 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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