4bpk | pdb_00004bpk

Bcl-xL bound to alpha beta Puma BH3 peptide 5

spinqualitylabelsall models 4bpk, resolution 1.76Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bpk is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.756Å Ligands: ACE, AHP, B3A, B3D, B3E, B3Q, CD, EDO, HR7, HT7, NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function B2CL1_HUMAN Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis. Isoform Bcl-X(S) promotes apoptosis. Publication Abstract from PubMed 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. Structure-guided rational design of alpha/beta-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.,Smith BJ, Lee EF, Checco JW, Evangelista M, Gellman SH, Fairlie WD Chembiochem. 2013 Sep 2;14(13):1564-72. doi: 10.1002/cbic.201300351. Epub 2013, Aug 8. PMID:23929624 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also B-cell lymphoma proteins 3D structures

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