The structure of the BIR3 domain of cIAP1 in complex with the N-terminal peptides of SMAC and caspase-9

Journal Article · Wed Jun 24 04:00:00 EDT 2009 · Acta Crystallogr. D

DOI:https://doi.org/10.1107/S0907444908039243· OSTI ID:1018556

Kulathila, Raviraj; Vash, Brian; Sage, David; Cornell-Kennon, Susan; Wright, Kirk; Koehn, James; Stams, Travis; Clark, Kirk; Price, Allen ^[1]

---

1. (Novartis)

The inhibitor of apoptosis protein (IAP) family of molecules inhibit apoptosis through the suppression of caspase activity. It is known that the XIAP protein regulates both caspase-3 and caspase-9 through direct protein-protein interactions. Specifically, the BIR3 domain of XIAP binds to caspase-9 via a 'hotspot' interaction in which the N-terminal residues of caspase-9 bind in a shallow groove on the surface of XIAP. This interaction is regulated via SMAC, the N-terminus of which binds in the same groove, thus displacing caspase-9. The mechanism of suppression of apoptosis by cIAP1 is less clear. The structure of the BIR3 domain of cIAP1 (cIAP1-BIR3) in complex with N-terminal peptides from both SMAC and caspase-9 has been determined. The binding constants of these peptides to cIAP1-BIR3 have also been determined using the surface plasmon resonance technique. The structures show that the peptides interact with cIAP1 in the same way that they interact with XIAP: both peptides bind in a similar shallow groove in the BIR3 surface, anchored at the N-terminus by a charge-stabilized hydrogen bond. The binding data show that the SMAC and caspase-9 peptides bind with comparable affinities (85 and 48 nM, respectively).

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE Office of Science (SC)
• OSTI ID: 1018556
• Journal Information: Acta Crystallogr. D, Journal Name: Acta Crystallogr. D Journal Issue: (1) ; 01, 2009 Vol. 65; ISSN 0907-4449
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

08 HYDROGEN
APOPTOSIS
HYDROGEN
NEOPLASMS
PEPTIDES
PLASMONS
PROTEINS
RESIDUES
RESONANCE