2ort

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(New page: 200px<br /><applet load="2ort" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ort, resolution 1.87&Aring;" /> '''Murine Inducible Nit...)
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[[Image:2ort.gif|left|200px]]<br /><applet load="2ort" size="450" color="white" frame="true" align="right" spinBox="true"
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[[Image:2ort.gif|left|200px]]<br /><applet load="2ort" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2ort, resolution 1.87&Aring;" />
caption="2ort, resolution 1.87&Aring;" />
'''Murine Inducible Nitric Oxide Synthase Oxygenase Domain (Delta 114) 1-Benzo[1,3]dioxol-5-ylmethyl-3S-(4-imidazol-1-yl-phenoxy)-piperidine Complex'''<br />
'''Murine Inducible Nitric Oxide Synthase Oxygenase Domain (Delta 114) 1-Benzo[1,3]dioxol-5-ylmethyl-3S-(4-imidazol-1-yl-phenoxy)-piperidine Complex'''<br />
==Overview==
==Overview==
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By the screening of a combinatorial library for inhibitors of nitric oxide, (NO) formation by the inducible isoform of nitric oxide synthase (iNOS), using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified., Compounds were found to inhibit the dimerization of iNOS monomers, thus, preventing the formation of the dimeric, active form of the enzyme., Optimization led to the selection of the potent, selective, and orally, available iNOS dimerization inhibitor, 21b, which significantly, ameliorated adjuvant-induced arthritis in a rat model. Analysis of the, crystal structure of the 21b--iNOS monomer complex provided a, rationalization for both the SAR and the mechanism by which 21b blocks the, formation of the protein--protein interaction present in the dimeric form, of iNOS.
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By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
==About this Structure==
==About this Structure==
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2ORT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with HEM and 342 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2ORT OCA].
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2ORT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=342:'>342</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ORT OCA].
==Reference==
==Reference==
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[[Category: nos]]
[[Category: nos]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 13:16:41 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:21:51 2008''

Revision as of 16:21, 21 February 2008

Image:2ort.gif

2ort, resolution 1.87Å

Drag the structure with the mouse to rotate

Murine Inducible Nitric Oxide Synthase Oxygenase Domain (Delta 114) 1-Benzo[1,3]dioxol-5-ylmethyl-3S-(4-imidazol-1-yl-phenoxy)-piperidine Complex

Overview

By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.

About this Structure

2ORT is a Single protein structure of sequence from Mus musculus with and as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.

Reference

Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors., Davey DD, Adler M, Arnaiz D, Eagen K, Erickson S, Guilford W, Kenrick M, Morrissey MM, Ohlmeyer M, Pan G, Paradkar VM, Parkinson J, Polokoff M, Saionz K, Santos C, Subramanyam B, Vergona R, Wei RG, Whitlow M, Ye B, Zhao ZS, Devlin JJ, Phillips G, J Med Chem. 2007 Mar 22;50(6):1146-57. Epub 2007 Feb 23. PMID:17315988

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