3QMO

X-ray crystal structure of NS-398 bound to the cyclooxygenase channel of cyclooxygenase-2

Summary for 3QMO

• Entry DOI: 10.2210/pdb3qmo/pdb
• Related: 3HS5 3HS6 3HS7 3LN1 3NT1 6COX
• Descriptor: Prostaglandin G/H synthase 2, alpha-D-mannopyranose, 2-acetamido-2-deoxy-alpha-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: biological dimer, oxidoreductase, dimer, n-glycosylation, monotopic membrane protein
• Biological source: Mus musculus (mouse)
• Total number of polymer chains: 2
• Total formula weight: 144946.48

Authors

Vecchio, A.J.,Malkowski, M.G. (deposition date: 2011-02-04, release date: 2011-08-03, Last modification date: 2024-12-25)

Primary citation

Vecchio, A.J.,Malkowski, M.G.
The structure of NS-398 bound to cyclooxygenase-2.
J.Struct.Biol., 176:254-258, 2011

PubMed Abstract: The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate prostaglandin H(2) from arachidonic acid (AA) in the committed step of prostaglandin biogenesis and are the targets for nonsteroidal anti-inflammatory drugs (NSAIDs). N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) was the first in a series of isoform-selective drugs designed to preferentially inhibit COX-2, with the aim of ameliorating many of the toxic gastrointestinal side effects caused by conventional NSAID inhibition. We determined the X-ray crystal structure of murine COX-2 in complex with NS-398 utilizing synchrotron radiation to 3.0A resolution. NS-398 binds in the cyclooxygenase channel in a conformation that is different than that observed for other COX-2-selective inhibitors, such as celecoxib, with no discernible penetration into the side pocket formed in COX-2 by the isoform-specific substitutions of I434V, H513R, and I523V. Instead, the methanesulfonamide moiety of NS-398 interacts with the side chain of Arg-120 at the opening of the cyclooxygenase channel, similar to that observed for acidic, nonselective NSAIDs such as indomethacin and flurbiprofen. Our structure validates inhibitor studies that identified Arg-120 as a molecular determinant for time-dependent inhibition of COX-2 by NS-398.

PubMed: 21843643
DOI: 10.1016/j.jsb.2011.07.019

Experimental method

X-RAY DIFFRACTION (3 Å)