对接(动物)
化学
立体化学
苯并吡喃
活动站点
结合位点
同源建模
丙氨酸
酶
生物化学
氨基酸
医学
护理部
作者
Anthony L. Albiston,Vi Pham,Siying Ye,Ley Moy Ng,Rebecca A. Lew,Phillip E. Thompson,Jessica K. Holien,Craig J. Morton,Michael W. Parker,Siew Yeen Chai
出处
期刊:Molecular Pharmacology
[American Society for Pharmacology & Experimental Therapeutics]
日期:2010-07-13
卷期号:78 (4): 600-607
被引量:21
标识
DOI:10.1124/mol.110.065458
摘要
Inhibitors of insulin-regulated aminopeptidase (IRAP) improve memory and are being developed as a novel treatment for memory loss. In this study, the binding of a class of these inhibitors to human IRAP was investigated using molecular docking and site-directed mutagenesis. Four benzopyran-based IRAP inhibitors with different affinities were docked into a homology model of the catalytic site of IRAP. Two 4-pyridinyl derivatives orient with the benzopyran oxygen interacting with the Zn(2+) ion and a direct parallel ring-stack interaction between the benzopyran rings and Phe544. In contrast, the two 4-quinolinyl derivatives orient in a different manner, interacting with the Zn(2+) ion via the quinoline nitrogen, and Phe544 contributes an edge-face hydrophobic stacking point with the benzopyran moiety. Mutagenic replacement of Phe544 with alanine, isoleucine, or valine resulted in either complete loss of catalytic activity or altered hydrolysis velocity that was substrate-dependent. Phe544 is also important for inhibitor binding, because these mutations altered the K(i) in some cases, and docking of the inhibitors into the corresponding Phe544 mutant models revealed how the interaction might be disturbed. These findings demonstrate a key role of Phe544 in the binding of the benzopyran IRAP inhibitors and for optimal positioning of enzyme substrates during catalysis.
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