Crystal Structure of Human D-Dopachrome Tautomerase, a Homologue of Macrophage Migration Inhibitory Factor, at 1.54 Å Resolution
详细信息 查看全文
- 作者：Hiroshi Sugimoto ; Masae Taniguchi ; Atsushi Nakagawa ; Isao Tanaka ; Masaki Suzuki ; and Jun Nishihira
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：March 16, 1999
- 年：1999
- 卷：38
- 期：11
- 页码：3268 - 3279
- 全文大小：504K
- 年卷期：v.38,no.11(March 16, 1999)
- ISSN：1520-4995
文摘
D-Dopachrome tautomerase shares a low homologous amino acid sequence (33% homology)with the macrophage migration inhibitory factor (MIF) and possesses similar tautomerase activity as well.MIF is a cytokine involved in inflammatory reactions and immune responses. Whereas recent studieshave identified MIF as a pituitary hormone and immunoregulator, much less is known about the structuralbasis of these physiological functions and the real significance of tautomerase activity. Therefore, interestin the structure-function relationship between D-dopachrome tautomerase and MIF has increased, especiallywith regard to inflammation and immune responses. We have determined the X-ray crystal structure ofhuman D-dopachrome tautomerase at 1.54 Å resolution. D-Dopachrome tautomerase folds to form ahomotrimer that has extensive contact between subunits by intersubunit 
-sheets. Its overall topology andtrimeric formations are similar to those of human MIF. The N-terminal proline is located at the bottomof a positively charged pocket in which the conformations of Lys32 and Ser63 are highly conserved.These positively charged properties are also seen in the active site pocket of human MIF, bacterial5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), and 4-oxalocrotonate tautomerase (4-OT). Adetailed comparison of these structures revealed significant differences in the environment around thepotential active site, the intersubunit contacts, and charge distribution on the molecular surface. It can beconcluded that these features are related to the physiological role and tautomerase activity of MIF andD-dopachrome tautomerase. The present structural study could be helpful for designing effective inhibitorsthat modulate immunoregulatory and hormone-like effects.
-sheets. Its overall topology andtrimeric formations are similar to those of human MIF. The N-terminal proline is located at the bottomof a positively charged pocket in which the conformations of Lys32 and Ser63 are highly conserved.These positively charged properties are also seen in the active site pocket of human MIF, bacterial5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), and 4-oxalocrotonate tautomerase (4-OT). Adetailed comparison of these structures revealed significant differences in the environment around thepotential active site, the intersubunit contacts, and charge distribution on the molecular surface. It can beconcluded that these features are related to the physiological role and tautomerase activity of MIF andD-dopachrome tautomerase. The present structural study could be helpful for designing effective inhibitorsthat modulate immunoregulatory and hormone-like effects.