X-RAY AND NMR STRUCTURE OF HUMAN BCL-X(L), AN INHIBITOR OF PROGRAMMEDCELL-DEATH

THE Bcl-2 family of proteins regulate programmed cell death by an unkn own mechanism(1). Here we describe the crystal and solution structures of a Bcl-2 family member, Bcl-x(L) (ref. 2). The structures consist o f two central, primarily hydrophobic alpha-helices, which are surround ed by amphipathic helices. A 60-residue loop connecting helices alpha 1 and alpha 2 was found to be flexible and non-essential for anti-apop totic activity. The three functionally important Bcl-2 homology region s (BH1, BH2 and BH3)(3-5) are in close spatial proximity and form an e longated hydrophobic cleft that may represent the binding site for oth er Bcl-2 family members. The arrangement of the alpha-helices in Bcl-x (L) is reminiscent of the membrane translocation domain of bacterial t oxins, in particular diphtheria toxin and the colicins(6). The structu ral similarity may provide a clue to the mechanism of action of the Bc l-2 family of proteins.