4BPK
Bcl-xL bound to alpha beta Puma BH3 peptide 5
Summary for 4BPK
| Entry DOI | 10.2210/pdb4bpk/pdb |
| Related | 4BPI 4BPJ |
| Descriptor | BCL-2-LIKE PROTEIN 1, ALPHA BETA BH3-PEPTIDE, CADMIUM ION, ... (5 entities in total) |
| Functional Keywords | apoptosis |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Total number of polymer chains | 4 |
| Total formula weight | 42475.84 |
| Authors | Smith, B.J.,Lee, E.F.,Checco, J.W.,Gellman, S.H.,Fairlie, W.D. (deposition date: 2013-05-27, release date: 2014-04-09, Last modification date: 2024-05-15) |
| Primary citation | Smith, B.J.,Lee, E.F.,Checco, J.W.,Evangelista, M.,Gellman, S.H.,Fairlie, W.D. Structure-Guided Rational Design of Alpha/Beta-Peptide Foldamers with High Affinity for Bcl-2 Family Prosurvival Proteins. Chembiochem, 14:1564-, 2013 Cited by PubMed Abstract: We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-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 α/β-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 α residues of the original α/β 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 α/β-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. PubMed: 23929624DOI: 10.1002/CBIC.201300351 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.756 Å) |
Structure validation
Download full validation report
