STRUCTURE OF Bcl-X_L, A DOMINANT INHIBITOR OF PROGRAMMED CELL DEATH. Steven W. Muchmore¹, Micheal Sattler², Heng Liang², Robert P Meadows², John E. Harlan², David Nettesheim², Brian Chang³, Craig B. Thompson³, Sui-Lam Wong⁴, Shi-Chung Ng⁴, Stephen W. Fesik², ¹Protein Crystallography, ²NMR Research, ³Aging and Degenerative Disease Research, Pharmaceutical Products Research Division, Abbott Laboratories Abbott Park, IL 60064, USA, ⁴Howard Hughes Medical Institute and Departments of Medicine, Molecula Genetics, and Cell Biology, University of Chicago, Chicago, IL 60637, USA.

The Bc1-2 family of proteins modulates programmed cell death (apoptosis) by an unknown mechanism. The structure of Bcl-X_L was solved by a combination of x-ray crystallographic and NMR spectroscopic techniques. The structure consists of a total of 7 alpha-helices, two of which form a central apolar pair. The remaining helices are amphipathic and flank the central pair. A loop of approximately 60 residues connecting the first two helices was found to be both flexible and dispersible for anti- apoptotic activity. Three functionally important homology domains (BH1, BH2, BH3) are located on the same face of the molecule and form a hydrophobic cleft which may represent the interaction site for proteins which promote apoptosis. Sequence alignments of other Bc1-2 family members suggests these proteins should exhibit the same overall fold. The Bcl-X_L structure is reminiscent of membrane translocation domains of bacterial toxins such as diphtheria toxin or colicin. This similarity suggests that the modulation of apoptosis by the Bcl-2, family of proteins may involve a membrane translocation event.