7EE8

The crystal structure of MIF bound to compound D5

7EE8 の概要

• エントリーDOI: 10.2210/pdb7ee8/pdb
• 分子名称: Macrophage migration inhibitory factor, CHLORIDE ION, 3-[(2R)-2-azanyl-1-oxidanyl-propyl]phenol, ... (5 entities in total)
• 機能のキーワード: tautomerase, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 37718.66

構造登録者

Fan, C.P.,Guo, D.Y.,Yang, L. (登録日: 2021-03-17, 公開日: 2025-03-26)

主引用文献

Yang, L.,Yang, C.,Wang, L.,Yang, Z.,Guo, D.,Fan, C.
Repurposing old drugs as novel inhibitors of human MIF from structural and functional analysis.
Bioorg.Med.Chem.Lett., 55:128445-128445, 2022

PubMed Abstract: Human macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine that plays multiple pleiotropic functions. It is considered as a promising therapeutic target for the infectious, autoimmune, and cardiovascular diseases and cancers. The development of MIF inhibitors has not been translated into clinical success despite decades of research. Given the time and cost of developing new drugs, existing drugs with clarified safety and pharmacokinetics are explored for their potential as novel MIF inhibitors. This study identified five known drugs that could inhibit MIF's tautomerase activity and MIF-mediated cell chemotaxis in RAW264.7 cells. It was found that compounds D2 (histamine), D5 (metaraminol), and D8 (nebivolol) exhibited micromolar-range inhibition potency close to the positive control ISO-1. Kinetics and the mechanism for inhibition were subsequently determined. Moreover, the detailed inhibitor-binding patterns were investigated by X-ray crystallography, computational molecular docking, and structure-based analysis. Therefore, this study elucidates the molecular mechanism of repurposed drugs acting on MIF and provides a structural foundation for lead optimization to promote the clinical development of MIF-targeted drugs.

PubMed: 34758374
DOI: 10.1016/j.bmcl.2021.128445

実験手法

X-RAY DIFFRACTION (1.22 Å)