7NM4

Solution structure of MLKL executioner domain in complex with a fragment

Summary for 7NM4

• Entry DOI: 10.2210/pdb7nm4/pdb
• NMR Information: BMRB: 34604
• Descriptor: Mixed lineage kinase domain-like protein, (~{S})-1~{H}-benzimidazol-2-yl-(4-propan-2-ylphenyl)methanol (2 entities in total)
• Functional Keywords: necroptosis, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18451.30

Authors

Ruebbelke, M.,Bauer, M.,Hamilton, J.,Binder, F.,Nar, H.,Zeeb, M. (deposition date: 2021-02-23, release date: 2021-09-22, Last modification date: 2024-06-19)

Primary citation

Rubbelke, M.,Hamilton, J.,Binder, F.,Bauer, M.,King, J.,Nar, H.,Zeeb, M.
Discovery and Structure-Based Optimization of Fragments Binding the Mixed Lineage Kinase Domain-like Protein Executioner Domain.
J.Med.Chem., 64:15629-15638, 2021

PubMed Abstract: Necroptosis is a form of programmed cell death that in case of misregulation can lead to inflammatory diseases. Mixed lineage kinase domain-like protein (MLKL), the effector protein in the canonical necroptosis signaling pathway, becomes activated by phosphorylation. Here, we report the identification of novel reversible binders of the MLKL executioner domain by a protein NMR-detected fragment-based screen. Determination of protein fragment costructures using NMR spectroscopy revealed a small molecule binding site that is distinct from the previously identified binding site of covalent MLKL inhibitors. Affinity optimization of the initially prioritized hit with millimolar affinity was achieved by NMR-guided structure-based design and yielded fragment-like molecules with a of 50 μM. Furthermore, we demonstrate that the improved fragment competes for the same binding site as nonyl-maltoside, a detergent that in conjunction with phytic acid activates the MLKL executioner domain.

PubMed: 34672548
DOI: 10.1021/acs.jmedchem.1c00686

Experimental method

SOLUTION NMR