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

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 recentl...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Morena Miciaccia, Benny Danilo Belviso, Mariaclara Iaselli, Gino Cingolani, Savina Ferorelli, Marianna Cappellari, Paola Loguercio Polosa, Maria Grazia Perrone, Rocco Caliandro, Antonio Scilimati
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e348145f07bc4650920473b1d5b3a4fd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e348145f07bc4650920473b1d5b3a4fd
record_format	dspace
spelling	oai:doaj.org-article:e348145f07bc4650920473b1d5b3a4fd2021-12-02T16:23:22ZThree-dimensional structure of human cyclooxygenase (hCOX)-110.1038/s41598-021-83438-z2045-2322https://doaj.org/article/e348145f07bc4650920473b1d5b3a4fd2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83438-zhttps://doaj.org/toc/2045-2322Abstract 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.Morena MiciacciaBenny Danilo BelvisoMariaclara IaselliGino CingolaniSavina FerorelliMarianna CappellariPaola Loguercio PolosaMaria Grazia PerroneRocco CaliandroAntonio ScilimatiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Morena Miciaccia Benny Danilo Belviso Mariaclara Iaselli Gino Cingolani Savina Ferorelli Marianna Cappellari Paola Loguercio Polosa Maria Grazia Perrone Rocco Caliandro Antonio Scilimati Three-dimensional structure of human cyclooxygenase (hCOX)-1
description	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.
format	article
author	Morena Miciaccia Benny Danilo Belviso Mariaclara Iaselli Gino Cingolani Savina Ferorelli Marianna Cappellari Paola Loguercio Polosa Maria Grazia Perrone Rocco Caliandro Antonio Scilimati
author_facet	Morena Miciaccia Benny Danilo Belviso Mariaclara Iaselli Gino Cingolani Savina Ferorelli Marianna Cappellari Paola Loguercio Polosa Maria Grazia Perrone Rocco Caliandro Antonio Scilimati
author_sort	Morena Miciaccia
title	Three-dimensional structure of human cyclooxygenase (hCOX)-1
title_short	Three-dimensional structure of human cyclooxygenase (hCOX)-1
title_full	Three-dimensional structure of human cyclooxygenase (hCOX)-1
title_fullStr	Three-dimensional structure of human cyclooxygenase (hCOX)-1
title_full_unstemmed	Three-dimensional structure of human cyclooxygenase (hCOX)-1
title_sort	three-dimensional structure of human cyclooxygenase (hcox)-1
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e348145f07bc4650920473b1d5b3a4fd
work_keys_str_mv	AT morenamiciaccia threedimensionalstructureofhumancyclooxygenasehcox1 AT bennydanilobelviso threedimensionalstructureofhumancyclooxygenasehcox1 AT mariaclaraiaselli threedimensionalstructureofhumancyclooxygenasehcox1 AT ginocingolani threedimensionalstructureofhumancyclooxygenasehcox1 AT savinaferorelli threedimensionalstructureofhumancyclooxygenasehcox1 AT mariannacappellari threedimensionalstructureofhumancyclooxygenasehcox1 AT paolaloguerciopolosa threedimensionalstructureofhumancyclooxygenasehcox1 AT mariagraziaperrone threedimensionalstructureofhumancyclooxygenasehcox1 AT roccocaliandro threedimensionalstructureofhumancyclooxygenasehcox1 AT antonioscilimati threedimensionalstructureofhumancyclooxygenasehcox1
_version_	1718384142280818688

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

Ejemplares similares