Programmed cell death, apoptosis, is a biological mechanism by which dangerous cells are killed. Commitment to this process is governed by the Bcl-2 proteins family, which respond to cellular stresses. The proteins within this family can be divided in three sub-categories according to their function. One subgroup, the BH3-only proteins, are upregulated upon cellular stresses and initiate apoptosis through interactions with other Bcl-2 family members. One very potent BH3-only protein, Bim, can directly activate the pro-apoptotic Bax or Bak proteins. Upon activation these proteins oligomerize at the mitochondrial outer membrane and provoke its permeabilization.

The structural details of the Bcl-2 family of proteins have not yet been fully characterized, and in particular, the nature by which BH3-only proteins activate Bax and Bak remains controversial. In attempts to crystallize the Bax protein in complex with the Bim BH3 we obtained crystals of the Bim BH3 alone. These crystals diffracted to a resolution of 1.3Å but no molecular replacement solution was found. The structure was eventually solved using the ARCIMBOLDO program. The structure revealed an unexpected tetrameric arrangement. Importantly, the helical face responsible for Bim pro-apoptotic activity is hidden within the tetramer suggesting a mechanism by which oligomerisation could regulate Bim activity.