3KJ2

Mcl-1 in complex with Bim BH3 mutant F4aE

Summary for 3KJ2

• Entry DOI: 10.2210/pdb3kj2/pdb
• Related: 2PQK 3KJ0 3KJ2
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-like protein 11, ZINC ION, ... (5 entities in total)
• Functional Keywords: bcl-2, bh3, apoptosis, protein-peptide complex, alternative splicing, cytoplasm, developmental protein, differentiation, isopeptide bond, membrane, mitochondrion, nucleus, phosphoprotein, polymorphism, transmembrane, ubl conjugation
• Biological source: Homo sapiens (human); 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: 21040.11

Authors

Fire, E.,Grant, R.A.,Keating, A.E. (deposition date: 2009-11-02, release date: 2010-02-16, Last modification date: 2021-10-13)

Primary citation

Fire, E.,Gulla, S.V.,Grant, R.A.,Keating, A.E.
Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes.
Protein Sci., 19:507-519, 2010

PubMed Abstract: Mcl-1 is an antiapoptotic Bcl-2-family protein that protects cells against death. Structures of Mcl-1, and of other anti-apoptotic Bcl-2 proteins, reveal a surface groove into which the alpha-helical BH3 regions of certain proapoptotic proteins can bind. Despite high overall structural conservation, differences in this groove afford binding specificity that is important for the mechanism of Bcl-2 family function. We report the crystal structure of human Mcl-1 bound to a BH3 peptide derived from human Bim and the structures for three complexes that accommodate large physicochemical changes at conserved Bim sites. The mutations had surprisingly modest effects on complex stability, and the structures show that Mcl-1 can undergo small changes to accommodate the mutant ligands. For example, a shift in a leucine side chain fills a hole left by an isoleucine-to-alanine mutation at the first hydrophobic buried position of Bim BH3. Larger changes are also observed, with shifting of helix alpha3 accommodating an isoleucine-to-tyrosine mutation at this same position. We surveyed the variation in available Mcl-1 and Bcl-x(L) structures and observed moderate flexibility that is likely critical for facilitating interactions of diverse BH3-only proteins with Mcl-1. With the antiapoptotic Bcl-2 family members attracting significant attention as therapeutic targets, these structures contribute to our growing understanding of how specificity is achieved and can help to guide the design of novel inhibitors that target Mcl-1.

PubMed: 20066663
DOI: 10.1002/pro.329

Experimental method

X-RAY DIFFRACTION (2.351 Å)