The different specific beneficial effects of Cyclooxygenase (COX)-1 and -2 inhibitors on human health have been known since the Nobel Laureate Prof. John Vane proven the existence of the COX-2. COXs are individually expressed in neurological and neurodegenerative diseases, and different types of cancer as well. More in-depth knowledge of the biology, structure and function of cyclooxygenase is required to plan pre-clinical studies. All the published structural works concern ovine (o) COX-1 (PDB ID: 3N8V), exploited for decades as a surrogate for the human (h) enzyme, more difficult to produce in milligrams quantities and recalcitrant to crystallization1. Herein, we present the 3.36 Å resolution X-ray crystal structure of the long-sought structure of hCOX-1 (PDB ID: 6Y3C) and relevant difference of the crystal structure of hCOX-1 and oCOX-1. Specifically, we also determined the amino acidic residues that, by changing their orientation, induce large variations in the position of neighboring residues due to the movement of the hinges. Conformations of Thr322, Pro218 and Ser126 in hCOX-1 and in the crystal structure of oCOX-1 are quite different, inducing the respective inhibitors to have different chemical characteristics. In summary, the 3D structure of hCOX-1 presented here will support, as main aim of this study, the development of probe targeting hCOX-1 for unmet clinical diagnosis of disease in which hCOX-1 is a biomarker.

Comparative Structural Analysis of hCOX‑1 and oCOX‑1 Isoenzymes

M. Miciaccia;B. D. Belviso;R. Caliandro;S. Ferorelli;M. G. Perrone;A. Scilimati
2021-01-01

Abstract

The different specific beneficial effects of Cyclooxygenase (COX)-1 and -2 inhibitors on human health have been known since the Nobel Laureate Prof. John Vane proven the existence of the COX-2. COXs are individually expressed in neurological and neurodegenerative diseases, and different types of cancer as well. More in-depth knowledge of the biology, structure and function of cyclooxygenase is required to plan pre-clinical studies. All the published structural works concern ovine (o) COX-1 (PDB ID: 3N8V), exploited for decades as a surrogate for the human (h) enzyme, more difficult to produce in milligrams quantities and recalcitrant to crystallization1. Herein, we present the 3.36 Å resolution X-ray crystal structure of the long-sought structure of hCOX-1 (PDB ID: 6Y3C) and relevant difference of the crystal structure of hCOX-1 and oCOX-1. Specifically, we also determined the amino acidic residues that, by changing their orientation, induce large variations in the position of neighboring residues due to the movement of the hinges. Conformations of Thr322, Pro218 and Ser126 in hCOX-1 and in the crystal structure of oCOX-1 are quite different, inducing the respective inhibitors to have different chemical characteristics. In summary, the 3D structure of hCOX-1 presented here will support, as main aim of this study, the development of probe targeting hCOX-1 for unmet clinical diagnosis of disease in which hCOX-1 is a biomarker.
978-88-94952-26-1
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/414552
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