AI Article Synopsis
- Necroptosis is a programmed cell death process that, if not properly regulated, can cause inflammatory diseases.
- Researchers identified new reversible binders for the MLKL protein, which is essential in the necroptosis pathway, using NMR-based methods.
- They improved the initial weak binding of these fragments through structure-based design and showed that the best fragments compete with both a detergent and a natural compound that activate MLKL.
Article 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.1c00686 | DOI Listing |
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