7ya5
Crystal structure analysis of cp1 bound BCL2/G101V
Structural highlights
DiseaseBCL2_HUMAN Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. FunctionBCL2_HUMAN Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).[1] Publication Abstract from PubMedOverexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-X(L) 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(L), 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(L) A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-X(L) by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics. Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-X(L) by engaging a single-residue discrepancy.,Li 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 Nat Commun. 2024 Feb 17;15(1):1476. doi: 10.1038/s41467-024-45848-1. PMID:38368459[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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