INHIBITION OF MACROPHAGE MIGRATION INHIBITORY FACTOR

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。巨噬细胞迁移抑制因子（Macrophage Migration Inhibitory Factor， MIF）是一种促炎细胞因子，可以抵消糖皮质激素的抗炎作用（Calandra and Bucala J. Inflammation, 47, pg. 39, 1995）。过度的MIF活性与许多疾病有关，包括感染性休克（Bernhagen等）。Nature 365，第756页，1993年)，关节炎Mikulowska等人。J. Immunology (158), pg. 5514, 1997)和癌症（Ren et al.）。安。外科医生242号，55页，2005年)。MIF也被发现可以增强大鼠的胰岛素分泌（Waeber等人）。PNAS 94，第4782页，1997)。MIF不仅是细胞因子，而且还具有催化活性。虽然所有已知的催化活性都涉及非生理性底物，但抑制催化活性位点会抑制其促炎功能（Lubetsky等）。生物。化学277，第24976页，2002年)。我们得到了具有共价结合抑制剂的1.75埃结构的MIF。我们希望得到一个更高分辨率的结构，以便更清楚地识别反应中间态或过渡态。鉴定这种中间体可能有助于阐明抑制的机制。

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.