3QH0

X-ray crystal structure of palmitic acid bound to the cyclooxygenase channel of cyclooxygenase-2

Summary for 3QH0

• Entry DOI: 10.2210/pdb3qh0/pdb
• Related: 1CVU 1DIY 3HS5 3HS6 3HS7 5COX
• Descriptor: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose, octyl beta-D-glucopyranoside, ... (12 entities in total)
• Functional Keywords: biological dimer, oxidoreductase, n-glycosylation, monotopic membrane protein
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 2
• Total formula weight: 145419.34

Authors

Vecchio, A.J.,Malkowski, M.G. (deposition date: 2011-01-25, release date: 2011-04-13, Last modification date: 2024-11-27)

Primary citation

Dong, L.,Vecchio, A.J.,Sharma, N.P.,Jurban, B.J.,Malkowski, M.G.,Smith, W.L.
Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer.
J.Biol.Chem., 286:19035-19046, 2011

PubMed Abstract: Prostaglandin endoperoxide H synthases 1 and 2, also known as cyclooxygenases (COXs) 1 and 2, convert arachidonic acid (AA) to prostaglandin endoperoxide H(2). Prostaglandin endoperoxide H synthases are targets of nonspecific nonsteroidal anti-inflammatory drugs and COX-2-specific inhibitors called coxibs. PGHS-2 is a sequence homodimer. Each monomer has a peroxidase and a COX active site. We find that human PGHS-2 functions as a conformational heterodimer having a catalytic monomer (E(cat)) and an allosteric monomer (E(allo)). Heme binds tightly only to the peroxidase site of E(cat), whereas substrates, as well as certain inhibitors (e.g. celecoxib), bind the COX site of E(cat). E(cat) is regulated by E(allo) in a manner dependent on what ligand is bound to E(allo). Substrate and nonsubstrate fatty acids (FAs) and some COX inhibitors (e.g. naproxen) preferentially bind to the COX site of E(allo). AA can bind to E(cat) and E(allo), but the affinity of AA for E(allo) is 25 times that for E(cat). Palmitic acid, an efficacious stimulator of human PGHS-2, binds only E(allo) in palmitic acid/murine PGHS-2 co-crystals. Nonsubstrate FAs can potentiate or attenuate actions of COX inhibitors depending on the FA and whether the inhibitor binds E(cat) or E(allo). Our studies suggest that the concentration and composition of the free FA pool in the environment in which PGHS-2 functions in cells, the FA tone, is a key factor regulating PGHS-2 activity and its responses to COX inhibitors. We suggest that differences in FA tone occurring with different diets will likely affect both base-line prostanoid synthesis and responses to COX inhibitors.

PubMed: 21467029
DOI: 10.1074/jbc.M111.231969

Experimental method

X-RAY DIFFRACTION (2.1 Å)