5JW1

Crystal structure of Celecoxib bound to S121P murine COX-2 mutant

Summary for 5JW1

• Entry DOI: 10.2210/pdb5jw1/pdb
• Related: 5JVY 5JVZ
• Descriptor: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING CO, ... (7 entities in total)
• Functional Keywords: cyclooxygenase, cox-2, celebrex, coxib, celecoxib, oxidoreductase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 131225.04

Authors

Malkowski, M.G.,Orlando, B.J. (deposition date: 2016-05-11, release date: 2016-10-26, Last modification date: 2023-09-27)

Primary citation

Dong, L.,Yuan, C.,Orlando, B.J.,Malkowski, M.G.,Smith, W.L.
Fatty Acid Binding to the Allosteric Subunit of Cyclooxygenase-2 Relieves a Tonic Inhibition of the Catalytic Subunit.
J.Biol.Chem., 291:25641-25655, 2016

PubMed Abstract: Prostaglandin endoperoxide H synthase-2 (PGHS-2), also called cyclooxygenase-2 (COX-2), converts arachidonic acid to PGH PGHS-2 is a conformational heterodimer composed of allosteric (E) and catalytic (E) subunits. Fatty acids (FAs) bind to Arg-120 of E increasing to different degrees, depending on the FA, the V of its E partner. We report here that movement of helical residues 120-122 and loop residues 123-129 of E underlies the allosteric effects of FAs and allosteric COX-2 inhibitors, including naproxen and flurbiprofen. An S121P substitution in both PGHS-2 monomers yields a variant (S121P/S121P PGHS-2) that has 1.7-1.8 times the V of native PGHS-2 and is relatively insensitive to activation by FAs or inhibition by allosteric inhibitors. The S121P substitution in E is primarily responsible for these effects. In X-ray crystal structures, the Cα atoms of helical residues 119-122 of S121P/S121P PGHS-2 are displaced from their normal positions. Additionally, the S121P/S121P PGHS-2 variants in which Pro-127 and Ser-541 are replaced by cysteines spontaneously forms Cys-127 to Cys-541 cross-links between monomers. This is unlike the corresponding native PGHS-2 variant and suggests that S121P substitutions also unhinge the loop involving residues 123-129. We conclude the following: (a) the region involving residues 120-129 of unoccupied E tonically inhibits E; (b) binding of an activating FA (e.g. arachidonic, palmitic, or oleic acid) to E or an S121P substitution in E repositions this region to increase E activity; and (c) allosteric COX inhibitors act by preventing FA binding to E and additionally by relocating E residues to inhibit E.

PubMed: 27756840
DOI: 10.1074/jbc.M116.757310

Experimental method

X-RAY DIFFRACTION (2.822 Å)