4BPI: Mcl-1 Bound To Alpha Beta Puma Bh3 Peptide 2

We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported alpha/beta-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived alpha/beta-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three alpha residues of the original alpha/beta backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new alpha/beta-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.
PDB ID: 4BPIDownload
MMDB ID: 118966
PDB Deposition Date: 2013/5/27
Updated in MMDB: 2014/04
Experimental Method:
x-ray diffraction
Resolution: 1.98  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4BPI: tetrameric; determined by author and by software (PISA)
Molecular Components in 4BPI
Label Count Molecule
Proteins (4 molecules)
Fusion Protein Consisting of Induced Myeloid Leukemia Cell Differentiation Protein Mcl-1 Homolog
Molecule annotation
Alpha Beta Bh3peptide
Molecule annotation
Chemicals (8 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB