The 2.0 A resolution crystal structure of prostaglandin H2 synthase-1:: Structural insights into an unusual peroxidase
The 2.0 A resolution crystal structure of prostaglandin H2 synthase-1:: Structural insights into an unusual peroxidase
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DOI：
10.1016/j.jmb.2003.10.073
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发表时间：
2004-01-09
影响因子：
5.6
通讯作者：
Loll, PJ
中科院分区：
文献类型：
--
作者：
Gupta, K;Selinsky, BS;Loll, PJ
前列腺素H-2合酶（EC 1.14.99.1）是一种完整的膜酶，含有一个环氧合酶位点（非甾体抗炎药的靶点）和一个空间上不同的过氧化物酶位点。以前的晶体学研究，这一临床上重要的药物靶标已受到阻碍的低分辨率。我们在此展示了羊前列腺素H-2合酶-1与α-甲基-4-联苯乙酸-甲基-4-联苯乙酸（非甾体抗炎药氟比洛芬的脱氟类似物）复合物的2.0埃分辨率X射线晶体结构。洗涤剂分子被认为是结合到蛋白质的膜结合域，其位置表明该域可能渗透到脂质双层的深度。该酶的近端血红素配体His 388的血红素铁的过氧化物酶的关系是非典型的;铁-组氨酸键是异常长，并观察到大量的倾斜角之间的血红素和咪唑平面。一个分子的甘油，作为一种冷冻保护剂在衍射实验中，被认为是结合在过氧化物酶网站，提供了第一个在这个活性位点的任何配体的看法。从甘油结合中获得的见解可能在过氧化物酶特异性配体的设计中证明是有用的。(C)2003 Elsevier Ltd.保留所有权利。
Prostaglandin H-2 synthase (EC 1.14.99.1) is an integral membrane enzyme containing a cyclooxygenase site, which is the target for the non-steroidal anti-inflammatory drugs, and a spatially distinct peroxidase site. Previous crystallographic studies of this clinically important drug target have been hindered by low resolution. We present here the 2.0 Angstrom resolution X-ray crystal structure of ovine prostaglandin H-2 synthase-1 in complex with alpha-methyl-4-biphenylacetic-methyl-4-biphenylacetic acid, a defluorinated analog of the non- steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the proteins membrane-binding domain, and their positions suggest the depth to which this domain is likely to penetrate into the lipid bilayer. The relation of the enzyme's proximal heme ligand His388 to the heme iron is atypical for a peroxidase; the iron-histidine bond is unusually long and a substantial tilt angle is observed between the heme and imidazole planes. A molecule of glycerol, used as a cryoprotectant during diffraction experiments, is seen to bind in the peroxidase site, offering the first view of any ligand in this active site. Insights gained from glycerol binding may prove useful in the design of a peroxidase-specific ligand. (C) 2003 Elsevier Ltd. All rights reserved.