3KK6: Crystal Structure of Cyclooxygenase-1 in complex with celecoxib

Citation:
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.
PDB ID: 3KK6Download
MMDB ID: 155907
PDB Deposition Date: 2009/11/4
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.75  Å
Source Organism:
Similar Structures:
Biological Unit for 3KK6: dimeric; determined by author and by software (PISA)
Molecular Components in 3KK6
Label Count Molecule
Proteins (2 molecules)
2
Prostaglandin G/H Synthase 1(Gene symbol: PTGS1)
Molecule annotation
Chemicals (24 molecules)
1
2
2
7
3
3
4
2
5
3
6
2
7
4
8
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.