|3kk6, resolution 2.75Å ()|
|Ligands:||, , , , , , ,|
|Gene:||COX1, PTGS1 (Ovis aries)|
Crystal Structure of Cyclooxygenase-1 in complex with celecoxib
Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A(2) formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.
Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1., Rimon G, Sidhu RS, Lauver DA, Lee JY, Sharma NP, Yuan C, Frieler RA, Trievel RC, Lucchesi BR, Smith WL, Proc Natl Acad Sci U S A. 2009 Dec 1. PMID:19955429
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Rimon G, Sidhu RS, Lauver DA, Lee JY, Sharma NP, Yuan C, Frieler RA, Trievel RC, Lucchesi BR, Smith WL. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1. Proc Natl Acad Sci U S A. 2009 Dec 1. PMID:19955429