Three-dimensional structure of human cyclooxygenase (hCOX)-1.
Three-dimensional structure of human cyclooxygenase (hCOX)-1.
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DOI：
10.1038/s41598-021-83438-z
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发表时间：
2021-02-22
影响因子：
4.6
通讯作者：
Scilimati A
中科院分区：
文献类型：
--
作者：
Miciaccia M;Belviso BD;Iaselli M;Cingolani G;Ferorelli S;Cappellari M;Loguercio Polosa P;Perrone MG;Caliandro R;Scilimati A
数千年来，人们都知道环氧合酶 (COX) 抑制剂对人类健康的有益作用。然而，直到最近，COX，特别是 COX-1，才与多种人类疾病有关，例如癌症、心力衰竭、神经系统疾病和神经退行性疾病。 COX 催化前列腺素 (PG) 生物合成的第一步，是最重要的炎症介质之一。所有已发表的关于 COX-1 的结构研究都涉及绵羊同工酶，它比人类酶更容易以毫克量生产，并且很容易结晶。在这里，我们报告了长期寻找的人类环氧合酶-1 (hCOX-1) 的结构，我们将其精炼至 R/Rfree 为 20.82/26.37，分辨率为 3.36 Å。 hCOX-1 结构提供了酶活性位点以及对抑制剂/底物结合和催化活性至关重要的残基的详细图片。我们使用基于笛卡尔坐标、主链二面角和溶剂可及性的度量以及多变量方法，将 hCOX-1 晶体结构与绵羊 COX-1 和人类 COX-2 结构进行了比较。讨论了结构之间的差异和相似之处，重点是负责各种酶多样化的基序（一级结构、稳定性、催化活性和特异性）。 hCOX-1 的结构代表了开发新型、更具选择性、具有增强治疗潜力的 COX-1 抑制剂的重要一步。
The beneficial effects of Cyclooxygenases (COX) inhibitors on human health have been known for thousands of years. Nevertheless, COXs, particularly COX-1, have been linked to a plethora of human diseases such as cancer, heart failure, neurological and neurodegenerative diseases only recently. COXs catalyze the first step in the biosynthesis of prostaglandins (PGs) and are among the most important mediators of inflammation. All published structural work on COX-1 deals with the ovine isoenzyme, which is easier to produce in milligram-quantities than the human enzyme and crystallizes readily. Here, we report the long-sought structure of the human cyclooxygenase-1 (hCOX-1) that we refined to an R/Rfree of 20.82/26.37, at 3.36 Å resolution. hCOX-1 structure provides a detailed picture of the enzyme active site and the residues crucial for inhibitor/substrate binding and catalytic activity. We compared hCOX-1 crystal structure with the ovine COX-1 and human COX-2 structures by using metrics based on Cartesian coordinates, backbone dihedral angles, and solvent accessibility coupled with multivariate methods. Differences and similarities among structures are discussed, with emphasis on the motifs responsible for the diversification of the various enzymes (primary structure, stability, catalytic activity, and specificity). The structure of hCOX-1 represents an essential step towards the development of new and more selective COX-1 inhibitors of enhanced therapeutic potential.
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DOI：
10.1107/s0108767309035612
发表时间：
2009-11-01
影响因子：
1.8
作者：
Caliandro, Rocco;Carrozzini, Benedetta;Siliqi, Dritan
通讯作者：
Siliqi, Dritan
影响因子：
56.9
作者：
Malkowski, MG;Ginell, SL;Garavito, RM
通讯作者：
Garavito, RM
影响因子：
3.5
作者：
Colabufo, Nicola A.;Contino, Marialessandra;Perrone, Roberto
通讯作者：
Perrone, Roberto
影响因子：
6.1
作者：
Caliandro, Rocco;Belviso, Danilo Benny
通讯作者：
Belviso, Danilo Benny
影响因子：
3.4
作者：
Calvello R;Lofrumento DD;Perrone MG;Cianciulli A;Salvatore R;Vitale P;De Nuccio F;Giannotti L;Nicolardi G;Panaro MA;Scilimati A
通讯作者：
Scilimati A