1dd7

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(New page: 200px<br /><applet load="1dd7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dd7, resolution 2.25&Aring;" /> '''MURINE INDUCIBLE NIT...)
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'''MURINE INDUCIBLE NITRIC OXIDE SYNTHASE OXYGENASE DOMAIN (DELTA 114) (N-[(1,3-BENZODIOXOL-5-YL)METHYL]-1-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]-4-(METHOXYCARBONYL)-PIPERAZINE-2-ACETAMIDE COMPLEX'''<br />
'''MURINE INDUCIBLE NITRIC OXIDE SYNTHASE OXYGENASE DOMAIN (DELTA 114) (N-[(1,3-BENZODIOXOL-5-YL)METHYL]-1-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]-4-(METHOXYCARBONYL)-PIPERAZINE-2-ACETAMIDE COMPLEX'''<br />
==Overview==
==Overview==
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Potent and selective inhibitors of inducible nitric oxide synthase (iNOS), (EC ) were identified in an encoded combinatorial chemical library that, blocked human iNOS dimerization, and thereby NO production. In a, cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had, low-nanomolar IC(50) values and thus were &gt;1,000-fold more potent than the, substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine., Biochemical studies confirmed that inhibitors caused accumulation of iNOS, monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d), approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed, by using a radioligand binding assay. Inhibitors were &gt;1,000-fold, selective for iNOS versus endothelial NOS dimerization in a cell-based, assay. The crystal structure of inhibitor bound to the monomeric iNOS, oxygenase domain revealed inhibitor-heme coordination and substantial, perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting, protein-protein interactions at the dimer interface. These results provide, a mechanism-based approach to highly selective iNOS inhibition. Inhibitors, were active in vivo, with ED(50) values of &lt;2 mg/kg in a rat model of, endotoxin-induced systemic iNOS induction. Thus, this class of, dimerization inhibitors has broad therapeutic potential in iNOS-mediated, pathologies.
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Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC ) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC(50) values and thus were &gt;1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d) approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were &gt;1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED(50) values of &lt;2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.
==About this Structure==
==About this Structure==
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1DD7 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 SO3, HEM and 1PM 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=1DD7 OCA].
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1DD7 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=SO3:'>SO3</scene>, <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=1PM:'>1PM</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=1DD7 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 Tue Nov 20 13:11:18 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:15:26 2008''

Revision as of 10:15, 21 February 2008

Image:1dd7.gif

1dd7, resolution 2.25Å

Drag the structure with the mouse to rotate

MURINE INDUCIBLE NITRIC OXIDE SYNTHASE OXYGENASE DOMAIN (DELTA 114) (N-[(1,3-BENZODIOXOL-5-YL)METHYL]-1-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]-4-(METHOXYCARBONYL)-PIPERAZINE-2-ACETAMIDE COMPLEX

Overview

Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC ) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC(50) values and thus were >1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d) approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were >1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED(50) values of <2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.

About this Structure

1DD7 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

Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry., McMillan K, Adler M, Auld DS, Baldwin JJ, Blasko E, Browne LJ, Chelsky D, Davey D, Dolle RE, Eagen KA, Erickson S, Feldman RI, Glaser CB, Mallari C, Morrissey MM, Ohlmeyer MH, Pan G, Parkinson JF, Phillips GB, Polokoff MA, Sigal NH, Vergona R, Whitlow M, Young TA, Devlin JJ, Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1506-11. PMID:10677491

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