7NM4

Solution structure of MLKL executioner domain in complex with a fragment

7NM4 の概要

• エントリーDOI: 10.2210/pdb7nm4/pdb
• NMR情報: BMRB: 34604
• 分子名称: Mixed lineage kinase domain-like protein, (~{S})-1~{H}-benzimidazol-2-yl-(4-propan-2-ylphenyl)methanol (2 entities in total)
• 機能のキーワード: necroptosis, lipid binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18451.30

構造登録者

Ruebbelke, M.,Bauer, M.,Hamilton, J.,Binder, F.,Nar, H.,Zeeb, M. (登録日: 2021-02-23, 公開日: 2021-09-22, 最終更新日: 2024-06-19)

主引用文献

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

実験手法

SOLUTION NMR