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.
Cossu
Federica
F
Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Via Celoria 26, I-20133, Milano, Italy.
Malvezzi
Francesca
F
Canevari
Giulia
G
Mastrangelo
Eloise
E
Lecis
Daniele
D
Delia
Domenico
D
Seneci
Pierfausto
P
Scolastico
Carlo
C
Bolognesi
Martino
M
Milani
Mario
M
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