6VBX

Crystal structure of Mcl-1 in complex with 138E12 peptide, Lys-covalent antagonist

Summary for 6VBX

• Entry DOI: 10.2210/pdb6vbx/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, Synthetic peptide (3 entities in total)
• Functional Keywords: mcl-1, apoptosis, 138e12 peptide, lys-covalent antagonists
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 19655.35

Authors

Pellecchia, M.,Perry, J.J.,Kenjic, N.,Assar, Z. (deposition date: 2019-12-19, release date: 2020-12-30, Last modification date: 2023-10-11)

Primary citation

Gambini, L.,Udompholkul, P.,Baggio, C.,Muralidharan, A.,Kenjic, N.,Assar, Z.,Perry, J.J.P.,Pellecchia, M.
Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1.
J.Med.Chem., 64:4903-4912, 2021

PubMed Abstract: Modulating 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.

PubMed: 33797903
DOI: 10.1021/acs.jmedchem.1c00005

Experimental method

X-RAY DIFFRACTION (1.95 Å)