2PQK: X-ray Crystal Structure Of Human Mcl-1 In Complex With Bim Bh3

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.
PDB ID: 2PQKDownload
MMDB ID: 46970
PDB Deposition Date: 2007/5/2
Updated in MMDB: 2017/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 2PQK: dimeric; determined by author and by software (PISA)
Molecular Components in 2PQK
Label Count Molecule
Proteins (2 molecules)
Induced Myeloid Leukemia Cell Differentiation Protein Mcl- 1(Gene symbol: MCL1)
Molecule annotation
BIM BH3 Peptide
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB