Document Type
Article
Publication Date
2-22-2021
Abstract
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.
Recommended Citation
Miciaccia, Morena; Belviso, Benny Danilo; Iaselli, Mariaclara; Cingolani, Gino; Ferorelli, Savina; Cappellari, Marianna; Loguercio Polosa, Paola; Perrone, Maria Grazia; Caliandro, Rocco; and Scilimati, Antonio, "Three-dimensional structure of human cyclooxygenase (hCOX)-1." (2021). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 182.
https://jdc.jefferson.edu/bmpfp/182
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
33619313
Language
English
Comments
This article is the author's final published version in Scientific Reports.
Volume 11, Issue 1, February 2021, Article number 4312.
The published version is available at https://doi.org/10.1038/s41598-021-83438-z
Copyright © The Author(s) 2021
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