The Structural Biology of Bcl-x(L)

Interactions between the pro-survival and pro-apoptotic members of the Bcl-2 family of proteins dictate whether a cell lives or dies. Much of our knowledge of the molecular details of these interactions has come from biochemical and structural studies on the pro-survival protein Bcl-x(L). The first high-resolution structure of any Bcl-2 family member was of Bcl-x(L), which revealed the conserved topology amongst all family members. Subsequent structures of Bcl-x(L) complexes with pro-apoptotic ligands demonstrated the general features of all pro-survival:pro-apoptotic complexes. Structural studies involving Bcl-x(L) were also the basis for the discovery of the first small-molecule pro-survival protein inhibitors, leading ultimately to the development of a new class of drugs now successfully used for cancer treatment in the clinic. This article will review our current knowledge of the structural biology of Bcl-x(L) and how this has impacted our understanding of the molecular details of the intrinsic apoptotic pathway.