title: The structure of XIAP BIR2: understanding the selectivity of the BIR domains.
abstract: 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.affiliation: Discovery Technologies, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Charles
authors.initials: C
authors.lastname: Belunis
authors.forename: Robert
authors.initials: R
authors.lastname: Crowther
authors.forename: Waleed
authors.initials: W
authors.lastname: Danho
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.forename: Barry
authors.initials: B
authors.lastname: Goggin
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Shirley
authors.initials: S
authors.lastname: Li
authors.forename: Stacy
authors.initials: S
authors.lastname: Remiszewski
authors.forename: Andrew
authors.initials: A
authors.lastname: Schutt
authors.forename: Manish K
authors.initials: MK
authors.lastname: Thakur
authors.forename: Saroj K
authors.initials: SK
authors.lastname: Singh
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Rajat
authors.initials: R
authors.lastname: Pandey
authors.forename: Rajiv
authors.initials: R
authors.lastname: Tyagi
authors.forename: Ramachandraiah
authors.initials: R
authors.lastname: Gosu
authors.forename: Ajith V
authors.initials: AV
authors.lastname: Kamath
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuglstatter
mesh_terms: D000595:Amino Acid Sequence; D001059:Apoproteins / Q000737:chemistry / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000737:chemistry* / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D017924:Nucleopolyhedroviruses / Q000737:chemistry* / Q000235:genetics; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000235:genetics
chemical_list: D001059:Apoproteins; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D014764:Viral Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D053148:Caspase 3
keywords: AVPI; BIR domains; SMAC; XIAP; apoptosis; caspases; extrinsic pathway; inhibitor of apoptosis; peptide complex