The structure of Mcl-1 in complex with the Bim BH3 peptide at 1.55 A resolution

Structural Biology, Walter & Eliza Hall Institute
â—‹Peter E Czabotar Erinna F Lee Marco Evangelista David C Huang Walter D Fairlie Peter M Colman

Mcl-1 is a member of the Bcl-2 family of proteins. These proteins are important in the regulation of programmed cell death, a process known as apoptosis. Apoptosis is essential for the development of multicellular organisms. Inappropriate regulation of apoptosis occurs during tumour formation and thus is an important target for cancer therapy.

Bim regulates the anti-apoptotic activity of Mcl-1 via its BH3 domain. We have crystallised the Mcl-1:Bim BH3 complex and determined its structure to 1.55 A resolution. We seek to exploit unique structural aspects of the complex by eventually identifying ligands that are able to bind Mcl-1 selectively and which might therefore have utility in treating cancers such as multiple myeloma where Mcl-1 expression is essential for the survival of the cancer cells.