Recognition of Smac-mimetic compounds by the BIR domain of cIAP1.
Inhibitor of apoptosis proteins (IAPs) are negative regulators of apoptosis. As IAPs are overexpressed in many tumors, where they confer chemoresistance, small molecules inactivating IAPs have been proposed as anticancer agents. Accordingly, a number of IAP-binding pro-apoptotic compounds that mimic the sequence corresponding to the N-terminal tetrapeptide of Smac/DIABLO, the natural endogenous IAPs inhibitor, have been developed. Here, we report the crystal structures of the BIR3 domain of cIAP1 in complex with Smac037, a Smac-mimetic known to bind potently to the XIAP-BIR3 domain and to induce degradation of cIAP1, and in complex with the novel Smac-mimetic compound Smac066. Thermal stability and fluorescence polarization assays show the stabilizing effect and the high affinity of both Smac037 and Smac066 for cIAP1- and cIAP2-BIR3 domains.
Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Via Celoria 26, I-20133, Milano, Italy.
Federica
F
Cossu
Francesca
F
Malvezzi
Giulia
G
Canevari
Eloise
E
Mastrangelo
Daniele
D
Lecis
Domenico
D
Delia
Pierfausto
P
Seneci
Carlo
C
Scolastico
Martino
M
Bolognesi
Mario
M
Milani
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins