Fig. 6: The 35 binding site in Bcl-2-xL is distinct from those of previously described Bcl-2 inhibitors and overlaps with the unique site that binds to the Beclin 1 BH3 domain N-terminus but not to Bax BH3.

a Superposition of ribbon diagrams of the Bcl-2-xL/35 complex (blue ribbon with 35 represented by yellow sticks) and the complex of a chimera in which the long flexible loop of Bcl-2(1-207) was replaced by a shorter sequence from the homologous loop of Bcl-xL [below referred to as Bcl-2-xL(1-207)] with ABT-737 (pink ribbon with ABT-737 represented by red sticks) (PDB accession number 6QGG). The position of residue 165, which corresponds to residue 206 of native Bcl-2, is indicated. b Superposition of ribbon diagrams of the Bcl-2-xL/35 complex (blue ribbon with 35 represented by yellow sticks) and various structures of Bcl-2-xL(1-207) or Bcl-xL bound to distinct inhibitors (pink ribbon with the inhibitors represented by red sticks) (PDB accession numbers 1YSG, 1YSN, 1YSW, 3INQ, 3QKD, 4IEH, 4LVT, 4LXD, 4MAN, 4QNQ, 6QGH, 6QGG, 7JMT). c Superposition of ribbon diagrams of Bcl-xL (blue ribbon) bound to the Beclin 1 BH3 domain (lime ribbon) with the structure of Bcl-2-xL(1-207) (pink ribbon) bound to the Bax BH3 domain (red ribbon) (PDB accession numbers 2P1L and 2XA0, respectively). Note that the structure of Bcl-2-xL(1-207) bound to the Beclin 1 BH3 domain (PDB accession number 5VAU) is very similar to that of the Bcl-xL/Beclin 1 BH3 complex; we show the latter because the former lacks T108 at the N-terminus of the BH3 domain. d Close-up view of the binding site of the N-termini of the BH3 domains (same structures as in c), with the molecular surface of Bcl-xL shown in blue, the Bax BH3 domain represented by red sticks and the Beclin 1 BH3 domain represented by a lime ribbon and sticks (carbon atoms in lime, nitrogen atoms in blue, oxygen atoms in red and sulfur atoms in yellow). Bcl-2-xL(1-207) is not shown. e Close-up view of the binding site of the Beclin 1 BH3 domain N-terminus (represented by sticks) in the molecular surface of Bcl-xL (same coloring as d) superimposed with the structure of the Bcl-2-xL/35 complex (35 represented by yellow sticks; Bcl-2-xL not shown). f Close-up view of the binding site of 35 (yellow sticks) on the molecular surface of the globular domain of Bcl-2-xL (blue; juxtamembrane region removed) superimposed with the structure of the Bcl-2-xL(1-207)/Bax BH3 complex (Bax BH3 represented by red sticks; Bcl-2-xL(1-207) not shown). Panels (e, f) show that much of the 35 binding site overlaps with the binding site of the Beclin 1 BH3 N-terminus that does not interact with the Bax BH3 domain.