Brad Sleebs - Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands

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      Publication Details (including relevant citation   information):

      The   Journal of Biological Chemistry (2009),   284(44),   30508-30517


      Antagonists of anti-apoptotic Bcl-2 family members hold promise   as cancer therapeutics. Apoptosis is triggered when a peptide   containing a BH3 motif or a small molecule BH3 peptidomimetic,   such as ABT 737, binds to the relevant Bcl-2 family members.   ABT-737 is an antagonist of Bcl-2, Bcl-x(L), and Bcl-w but not of   Mcl-1. Here we describe new structures of mutant BH3 peptides   bound to Bcl-x(L) and Mcl-1. These structures suggested a   rationale for the failure of ABT-737 to bind Mcl-1, but a   designed variant of ABT-737 failed to acquire binding affinity   for Mcl-1. Rather, it was selective for Bcl-x(L), a result   attributable in part to significant backbone refolding and   movements of helical segments in its ligand binding site. To date   there are few reported crystal structures of organic ligands in   complex with their pro-survival protein targets. Our structure of   this new organic ligand provided insights into the structural   transitions that occur within the BH3 binding groove,   highlighting significant differences in the structural properties   of members of the Bcl-2 pro-survival protein family. Such   differences are likely to influence and be important in the quest   for compounds capable of selectively antagonizing the different   family members.

      Address (URL): http://10.1074/jbc.M109.040725