6PEG

MIF with a allosteric inhibitor

6PEG の概要

• エントリーDOI: 10.2210/pdb6peg/pdb
• 分子名称: Macrophage migration inhibitory factor, ACETATE ION, GLYCEROL, ... (7 entities in total)
• 機能のキーワード: inhibitor, mif, drug discovery, 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: 38587.32

構造登録者

Asojo, O.A. (登録日: 2019-06-20, 公開日: 2019-11-27, 最終更新日: 2023-10-11)

主引用文献

Cirillo, P.F.,Asojo, O.A.,Khire, U.,Lee, Y.,Mootien, S.,Hegan, P.,Sutherland, A.G.,Peterson-Roth, E.,Ledizet, M.,Koski, R.A.,Anthony, K.G.
Inhibition of Macrophage Migration Inhibitory Factor by a Chimera of Two Allosteric Binders.
Acs Med.Chem.Lett., 11:1843-1847, 2020

PubMed Abstract: Human Macrophage Migration Inhibitory Factor (MIF) is a trimeric cytokine implicated in a number of inflammatory and autoimmune diseases and cancer. We previously reported that the dye p425 (Chicago Sky Blue), which bound MIF at the interface of two MIF trimers covering the tautomerase and allosteric pockets, revealed a unique strategy to block MIF's pro-inflammatory activities. Structural liabilities, including the large size, precluded p425 as a medicinal chemistry lead for drug development. We report here a rational design strategy linking only the fragment of p425 that binds over the tautomerase pocket to the core of ibudilast, a known MIF allosteric site-specific inhibitor. The chimeric compound, termed L2-4048, was shown by X-ray crystallography to bind at the allosteric and tautomerase sites as anticipated. L2-4048 retained target binding and blocked MIF's tautomerase CD74 receptor binding, and pro-inflammatory activities. Our studies lay the foundation for the design and synthesis of smaller and more drug-like compounds that retain the MIF inhibitory properties of this chimera.

PubMed: 33062162
DOI: 10.1021/acsmedchemlett.9b00351

実験手法

X-RAY DIFFRACTION (2 Å)