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Title: The structure of XIAP BIR2: understanding the selectivity of the BIR domains

The high-resolution crystal structures of apo and peptide-bound XIAP BIR2 are presented and compared with BIR3 structures to understand their selectivity. This crystal system can be used to determine the structures of BIR2–inhibitor complexes. XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain–caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3–caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2–caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2–tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.
Authors:
; ; ; ; ; ; ; ; ;  [1] ; ; ; ; ; ; ;  [2] ;  [1]
  1. Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110 (United States)
  2. Jubilant Biosys Ltd, Bangalore (India)
Publication Date:
OSTI Identifier:
22347822
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 69; Journal Issue: Pt 9; Other Information: PMCID: PMC3760131; PMID: 23999295; PUBLISHER-ID: mh5092; OAI: oai:pubmedcentral.nih.gov:3760131; Copyright (c) Lukacs et al. 2013; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; CRYSTAL STRUCTURE; CRYSTALS; DESIGN; FLEXIBILITY; INTERACTIONS; MOLECULES; NEOPLASMS; RESOLUTION