3KK6

Crystal Structure of Cyclooxygenase-1 in complex with celecoxib

Summary for 3KK6

• Entry DOI: 10.2210/pdb3kk6/pdb
• Descriptor: Prostaglandin G/H synthase 1, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: cox-1, cyclooxygenase, peroxidase, prostaglandin, heme, celecoxib, merohedral twinned, dioxygenase, disulfide bond, egf-like domain, endoplasmic reticulum, fatty acid biosynthesis, glycoprotein, iron, lipid synthesis, membrane, metal-binding, microsome, oxidoreductase, prostaglandin biosynthesis, transmembrane
• Biological source: Ovis aries (domestic sheep,lambs,wild sheep)
• Total number of polymer chains: 2
• Total formula weight: 133735.28

Authors

Sidhu, R.S. (deposition date: 2009-11-04, release date: 2009-12-15, Last modification date: 2024-11-20)

Primary citation

Rimon, G.,Sidhu, R.S.,Lauver, D.A.,Lee, J.Y.,Sharma, N.P.,Yuan, C.,Frieler, R.A.,Trievel, R.C.,Lucchesi, B.R.,Smith, W.L.
Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.
Proc.Natl.Acad.Sci.USA, 107:28-33, 2010

PubMed Abstract: 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.

PubMed: 19955429
DOI: 10.1073/pnas.0909765106

Experimental method

X-RAY DIFFRACTION (2.75 Å)