INHIBITION OF MACROPHAGE MIGRATION INHIBITORY FACTOR

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。巨噬细胞迁移抑制因子（MIF）是一种促炎细胞因子，其抵消糖皮质激素的抗炎活性（Calandra和Bucala J. Inflammation 47，第39页，1995）。过度的MIF活性与许多疾病有关，包括败血性休克（Bernardson等，Nature 365，pg.756，1993）、关节炎Mikulowska等，J. Immunology 158，pg.5514，1997）和癌症（Ren等，Ann.Surg.242，pg.55，2005）。还发现MIF增强大鼠的胰岛素分泌（Waeber等，PNAS 94，pg.4782，1997）。 MIF不仅是一种细胞因子，而且具有催化活性。尽管其所有已知的催化活性都涉及非生理底物，但抑制催化活性位点会抑制其促炎功能（Lubetsky等人，J. Biol. Chem. 277，pg.24976，2002）。我们有一个1.75埃的MIF结构与共价结合的抑制剂。我们希望获得更高分辨率的结构，以便更清楚地识别反应中间体或过渡态。该中间体的鉴定可能有助于阐明抑制机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine that counteracts the anti-inflammatory activities of glucocorticoids (Calandra and Bucala J. Inflammation 47, pg. 39, 1995). Excessive MIF activity has been implicated in a number of diseases, including septic shock (Bernhagen et al. Nature 365, pg. 756, 1993), arthritis Mikulowska et al. J. Immunology 158, pg. 5514, 1997) and cancer (Ren et al. Ann. Surg. 242, pg. 55,2005). MIF has also been found to enhance insulin secretion in rats (Waeber et al. PNAS 94, pg. 4782, 1997). Not only is MIF a cytokine, but it also has catalytic activity. Although all of its known catalytic activities involve non-physiological substrates, inhibiting the catalytic active-site inhibits its pro-inflammatory function (Lubetsky et al. J. Biol. Chem. 277, pg.24976, 2002). We have a 1.75 Angstrom structure of MIF with a covalently bound inhibitor. We hope to obtain a higher-resolution structure in order to identify the reaction intermediate, or transition state, more clearly. Identification of this intermediate may aid in elucidating a mechanism of inhibition.