1pxx

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[[Image:1pxx.gif|left|200px]]
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{{STRUCTURE_1pxx| PDB=1pxx | SCENE= }}
{{STRUCTURE_1pxx| PDB=1pxx | SCENE= }}
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'''CRYSTAL STRUCTURE OF DICLOFENAC BOUND TO THE CYCLOOXYGENASE ACTIVE SITE OF COX-2'''
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===CRYSTAL STRUCTURE OF DICLOFENAC BOUND TO THE CYCLOOXYGENASE ACTIVE SITE OF COX-2===
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==Overview==
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A variety of drugs inhibit the conversion of arachidonic acid to prostaglandin G2 by the cyclooxygenase (COX) activity of prostaglandin endoperoxide synthases. Several modes of inhibitor binding in the COX active site have been described including ion pairing of carboxylic acid containing inhibitors with Arg-120 of COX-1 and COX-2 and insertion of arylsulfonamides and sulfones into the COX-2 side pocket. Recent crystallographic evidence suggests that Tyr-385 and Ser-530 chelate polar or negatively charged groups in arachidonic acid and aspirin. We tested the generality of this binding mode by analyzing the action of a series of COX inhibitors against site-directed mutants of COX-2 bearing changes in Arg-120, Tyr-355, Tyr-348, and Ser-530. Interestingly, diclofenac inhibition was unaffected by the mutation of Arg-120 to alanine but was dramatically attenuated by the S530A mutation. Determination of the crystal structure of a complex of diclofenac with murine COX-2 demonstrates that diclofenac binds to COX-2 in an inverted conformation with its carboxylate group hydrogen-bonded to Tyr-385 and Ser-530. This finding represents the first experimental demonstration that the carboxylate group of an acidic non-steroidal anti-inflammatory drug can bind to a COX enzyme in an orientation that precludes the formation of a salt bridge with Arg-120. Mutagenesis experiments suggest Ser-530 is also important in time-dependent inhibition by nimesulide and piroxicam.
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(as it appears on PubMed at http://www.pubmed.gov), where 12925531 is the PubMed ID number.
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{{ABSTRACT_PUBMED_12925531}}
==About this Structure==
==About this Structure==
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Prostaglandin]]
[[Category: Prostaglandin]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 14:12:45 2008''

Revision as of 11:12, 29 July 2008

Image:1pxx.png

Template:STRUCTURE 1pxx

CRYSTAL STRUCTURE OF DICLOFENAC BOUND TO THE CYCLOOXYGENASE ACTIVE SITE OF COX-2

Template:ABSTRACT PUBMED 12925531

About this Structure

1PXX is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385., Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ, J Biol Chem. 2003 Nov 14;278(46):45763-9. Epub 2003 Aug 18. PMID:12925531

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