3IO9

BimL12Y in complex with Mcl-1

Summary for 3IO9

• Entry DOI: 10.2210/pdb3io9/pdb
• Related: 2nl9 3IO8
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 11, ZINC ION, ... (4 entities in total)
• Functional Keywords: apoptosis, alternative splicing, cytoplasm, developmental protein, differentiation, isopeptide bond, membrane, mitochondrion, nucleus, phosphoprotein, polymorphism, transmembrane, ubl conjugation
• Biological source: Mus musculus (Mouse); More
• Cellular location: Membrane ; Single-pass membrane protein : Q07820; Endomembrane system ; Peripheral membrane protein . Isoform BimEL: Mitochondrion. Isoform BimL: Mitochondrion. Isoform BimS: Mitochondrion. Isoform Bim-alpha1: Mitochondrion: O43521
• Total number of polymer chains: 2
• Total formula weight: 21813.93

Authors

Czabotar, P.E.,Lee, E.F.,Yang, H.,Sleebs, B.E.,Lessene, G.,Colman, P.M.,Smith, B.J.,Fairlie, W.D. (deposition date: 2009-08-14, release date: 2009-09-01, Last modification date: 2023-09-06)

Primary citation

Lee, E.F.,Czabotar, P.E.,Yang, H.,Sleebs, B.E.,Lessene, G.,Colman, P.M.,Smith, B.J.,Fairlie, W.D.
Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands.
J.Biol.Chem., 284:30508-30517, 2009

PubMed Abstract: 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.

PubMed: 19726685
DOI: 10.1074/jbc.M109.040725

Experimental method

X-RAY DIFFRACTION (2.4 Å)