1vaf
From Proteopedia
(New page: 200px<br /><applet load="1vaf" size="450" color="white" frame="true" align="right" spinBox="true" caption="1vaf, resolution 2.9Å" /> '''Inducible nitric oxid...) |
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| - | [[Image:1vaf.gif|left|200px]]<br /><applet load="1vaf" size=" | + | [[Image:1vaf.gif|left|200px]]<br /><applet load="1vaf" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1vaf, resolution 2.9Å" /> | caption="1vaf, resolution 2.9Å" /> | ||
'''Inducible nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477'''<br /> | '''Inducible nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The high level of amino acid conservation and structural similarity of the | + | The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested. |
==About this Structure== | ==About this Structure== | ||
| - | 1VAF 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 ZN, HEM, H4B and ARR 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:// | + | 1VAF 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=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=H4B:'>H4B</scene> and <scene name='pdbligand=ARR:'>ARR</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=1VAF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Fedorov, R.]] | [[Category: Fedorov, R.]] | ||
| - | [[Category: Ghosh, D | + | [[Category: Ghosh, D K.]] |
[[Category: Schlichting, I.]] | [[Category: Schlichting, I.]] | ||
[[Category: Vasan, R.]] | [[Category: Vasan, R.]] | ||
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[[Category: murine inosoxy inhibitor complex]] | [[Category: murine inosoxy inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:33:11 2008'' |
Revision as of 13:33, 21 February 2008
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Inducible nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477
Overview
The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.
About this Structure
1VAF 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
Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design., Fedorov R, Vasan R, Ghosh DK, Schlichting I, Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5892-7. Epub 2004 Apr 7. PMID:15071192
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