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Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design.(BIOCHEMISTRY)(Author abstract)(Report)

Gilbreth, Ryan N. ; Truong, Khue ; Madu, Ikenna ; Koide, Akiko ; Wojcik, John B. ; Li, Nan - Sheng ; Piccirilli, Joseph A. ; Chen, Yuan ; Koide, Shohei

Proceedings of the National Academy of Sciences of the United States, May 10, 2011, Vol.108(19), p.7751(6) [Tạp chí có phản biện]

ISSN: 0027-8424

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  • Nhan đề:
    Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design.(BIOCHEMISTRY)(Author abstract)(Report)
  • Tác giả: Gilbreth, Ryan N. ; Truong, Khue ; Madu, Ikenna ; Koide, Akiko ; Wojcik, John B. ; Li, Nan - Sheng ; Piccirilli, Joseph A. ; Chen, Yuan ; Koide, Shohei
  • Chủ đề: Proteins -- Research ; Bioengineering -- Research
  • Là 1 phần của: Proceedings of the National Academy of Sciences of the United States, May 10, 2011, Vol.108(19), p.7751(6)
  • Mô tả: 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 isoformspecific 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.sub.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. protein engineering | molecular recognition | posttranslational modification | antibody mimic | fibronectin type III domain doi/ 10.1073/pnas.1102294108
  • Ngôn ngữ: English
  • Số nhận dạng: ISSN: 0027-8424

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