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7Y90

Crystal Structure Analysis of cp1 bound BCL2

Summary for 7Y90
Entry DOI10.2210/pdb7y90/pdb
DescriptorApoptosis regulator Bcl-2, cp1 peptide, (2R)-3-[2-(aminomethyl)-3-azanyl-1-[4-[2-(2-chloranylethanoylamino)ethylcarbamoyl]phenyl]prop-1-enyl]sulfanyl-2-(carboxyamino)propanoic acid, ... (4 entities in total)
Functional Keywordsbcl2, cp1, complex, apoptosis
Biological sourceHomo sapiens (human)
More
Total number of polymer chains2
Total formula weight21277.11
Authors
Li, F.W. (deposition date: 2022-06-24, release date: 2023-11-15, Last modification date: 2024-10-23)
Primary citationLi, F.,Liu, J.,Liu, C.,Liu, Z.,Peng, X.,Huang, Y.,Chen, X.,Sun, X.,Wang, S.,Chen, W.,Xiong, D.,Diao, X.,Wang, S.,Zhuang, J.,Wu, C.,Wu, D.
Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-X L by engaging a single-residue discrepancy.
Nat Commun, 15:1476-1476, 2024
Cited by
PubMed Abstract: Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-X can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-X, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-X A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-X by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.
PubMed: 38368459
DOI: 10.1038/s41467-024-45848-1
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.09 Å)
Structure validation

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