1GD0

HUMAN MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)

1GD0 の概要

• エントリーDOI: 10.2210/pdb1gd0/pdb
• 関連するPDBエントリー: 1GCZ
• 分子名称: MACROPHAGE MIGRATION INHIBITORY FACTOR, SULFATE ION, CITRIC ACID, ... (4 entities in total)
• 機能のキーワード: mif, macrophage migration inhibitory factor, immune system
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P14174
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 41527.44

構造登録者

Kurihara, H.,Katayama, N. (登録日: 2000-08-24, 公開日: 2001-02-21, 最終更新日: 2023-10-25)

主引用文献

Orita, M.,Yamamoto, S.,Katayama, N.,Aoki, M.,Takayama, K.,Yamagiwa, Y.,Seki, N.,Suzuki, H.,Kurihara, H.,Sakashita, H.,Takeuchi, M.,Fujita, S.,Yamada, T.,Tanaka, A.
Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography.
J.Med.Chem., 44:540-547, 2001

PubMed Abstract: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.

PubMed: 11170644
DOI: 10.1021/jm000386o

実験手法

X-RAY DIFFRACTION (1.5 Å)