کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2828697 | 1162750 | 2011 | 5 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: The structure of NS-398 bound to cyclooxygenase-2 The structure of NS-398 bound to cyclooxygenase-2](/preview/png/2828697.png)
The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate prostaglandin H2 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 3.0 A 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.
Journal: Journal of Structural Biology - Volume 176, Issue 2, November 2011, Pages 254–258