6vbx
Crystal structure of Mcl-1 in complex with 138E12 peptide, Lys-covalent antagonistCrystal structure of Mcl-1 in complex with 138E12 peptide, Lys-covalent antagonist
Structural highlights
FunctionMCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[1] Publication Abstract from PubMedModulating disease-relevant protein-protein interactions (PPIs) using pharmacological tools is a critical step toward the design of novel therapeutic strategies. Over the years, however, targeting PPIs has proven a very challenging task owing to the large interfacial areas. Our recent efforts identified possible novel routes for the design of potent and selective inhibitors of PPIs using a structure-based design of covalent inhibitors targeting Lys residues. In this present study, we report on the design, synthesis, and characterizations of the first Lys-covalent BH3 peptide that has a remarkable affinity and selectivity for hMcl-1 over the closely related hBfl-1 protein. Our structural studies, aided by X-ray crystallography, provide atomic-level details of the inhibitor interactions that can be used to further translate these discoveries into novel generation, Lys-covalent pro-apoptotic agents. Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1.,Gambini L, Udompholkul P, Baggio C, Muralidharan A, Kenjic N, Assar Z, Perry JJP, Pellecchia M J Med Chem. 2021 Apr 22;64(8):4903-4912. doi: 10.1021/acs.jmedchem.1c00005. Epub , 2021 Apr 2. PMID:33797903[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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