Three-dimensional structure of human cyclooxygenase (hCOX)-1

DOI: 10.1038/s41598-021-83438-z

Authors: Morena Miciaccia (University of Bari “Aldo Moro”) , Benny Danilo Belviso (Consiglio Nazionale delle Ricerche) , Mariaclara Iaselli (University of Bari “Aldo Moro”) , Gino Cingolani (Thomas Jefferson University) , Savina Ferorelli (University of Bari “Aldo Moro”) , Marianna Cappellari (University of Bari “Aldo Moro”) , Paola Loguercio Polosa (University of Bari “Aldo Moro”) , Maria Grazia Perrone (University of Bari “Aldo Moro”) , Rocco Caliandro (Consiglio Nazionale delle Ricerche) , Antonio Scilimati (University of Bari “Aldo Moro”)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 11

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 15832

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.

Journal Keywords: Chromatography; Enzymes; Isolation, separation and purification; Membrane proteins; Protein purification; Structural biology; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Documents:
s41598-021-83438-z.pdf

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