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Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design.

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.

Pubmed ID: 21518904


  • Gilbreth RN
  • Truong K
  • Madu I
  • Koide A
  • Wojcik JB
  • Li NS
  • Piccirilli JA
  • Chen Y
  • Koide S


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 10, 2011

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01-GM090324
  • Agency: NIGMS NIH HHS, Id: R01-GM72688
  • Agency: NCI NIH HHS, Id: R21-CA132700
  • Agency: NIGMS NIH HHS, Id: T32GM007183-32A1

Mesh Terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Library
  • Peptides
  • Protein Binding
  • Protein Engineering
  • Protein Interaction Domains and Motifs
  • Protein Isoforms
  • SUMO-1 Protein
  • Saccharomyces cerevisiae Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitins