1ebv: Difference between revisions
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New page: left|200px<br /><applet load="1ebv" size="450" color="white" frame="true" align="right" spinBox="true" caption="1ebv, resolution 3.2Å" /> '''OVINE PGHS-1 COMPLEXE... |
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[[Image:1ebv.jpg|left|200px]]<br /><applet load="1ebv" size=" | [[Image:1ebv.jpg|left|200px]]<br /><applet load="1ebv" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1ebv, resolution 3.2Å" /> | caption="1ebv, resolution 3.2Å" /> | ||
'''OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID'''<br /> | '''OVINE PGHS-1 COMPLEXED WITH SALICYL HYDROXAMIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
Aspirin is unique among clinically used nonsteroidal antiinflammatory | Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors. | ||
==About this Structure== | ==About this Structure== | ||
1EBV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries] with NAG, SCL and HEM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] Full crystallographic information is available from [http:// | 1EBV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ovis_aries Ovis aries] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=SCL:'>SCL</scene> and <scene name='pdbligand=HEM:'>HEM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Prostaglandin-endoperoxide_synthase Prostaglandin-endoperoxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.99.1 1.14.99.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EBV OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Prostaglandin-endoperoxide synthase]] | [[Category: Prostaglandin-endoperoxide synthase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Connor, S | [[Category: Connor, S J.O.]] | ||
[[Category: Fitzgerald, D | [[Category: Fitzgerald, D J.]] | ||
[[Category: Loll, P | [[Category: Loll, P J.]] | ||
[[Category: Sharkey, C | [[Category: Sharkey, C T.]] | ||
[[Category: HEM]] | [[Category: HEM]] | ||
[[Category: NAG]] | [[Category: NAG]] | ||
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[[Category: monotopic membrane protein]] | [[Category: monotopic membrane protein]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:26:06 2008'' | ||
