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| | ==Structure of neuronal nitric oxide synthase heme domain in complex with 6,6'-(2,2'-(pyridine-3,5-diyl)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)== | | ==Structure of neuronal nitric oxide synthase heme domain in complex with 6,6'-(2,2'-(pyridine-3,5-diyl)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)== |
| - | <StructureSection load='3n5w' size='340' side='right' caption='[[3n5w]], [[Resolution|resolution]] 1.73Å' scene=''> | + | <StructureSection load='3n5w' size='340' side='right'caption='[[3n5w]], [[Resolution|resolution]] 1.73Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3n5w]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N5W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3N5W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3n5w]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N5W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N5W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=XFJ:6,6-(PYRIDINE-3,5-DIYLDIETHANE-2,1-DIYL)BIS(4-METHYLPYRIDIN-2-AMINE)'>XFJ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.73Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3n5p|3n5p]], [[3n5q|3n5q]], [[3n5r|3n5r]], [[3n5s|3n5s]], [[3n5t|3n5t]], [[3n5v|3n5v]], [[3n5x|3n5x]], [[3n5y|3n5y]], [[3n5z|3n5z]], [[3n60|3n60]], [[3n61|3n61]], [[3n62|3n62]], [[3n63|3n63]], [[3n64|3n64]], [[3n65|3n65]], [[3n66|3n66]], [[3n67|3n67]], [[3n68|3n68]], [[3n69|3n69]], [[3n6a|3n6a]], [[3n6b|3n6b]], [[3n6c|3n6c]], [[3n6d|3n6d]], [[3n6e|3n6e]], [[3n6f|3n6f]], [[3n6g|3n6g]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=XFJ:6,6-(PYRIDINE-3,5-DIYLDIETHANE-2,1-DIYL)BIS(4-METHYLPYRIDIN-2-AMINE)'>XFJ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NOS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3n5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5w OCA], [https://pdbe.org/3n5w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n5w RCSB], [https://www.ebi.ac.uk/pdbsum/3n5w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5w ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase_(NADPH_dependent) Nitric-oxide synthase (NADPH dependent)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3n5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n5w OCA], [http://pdbe.org/3n5w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3n5w RCSB], [http://www.ebi.ac.uk/pdbsum/3n5w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3n5w ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT]] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. | + | [https://www.uniprot.org/uniprot/NOS1_RAT NOS1_RAT] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Nitric Oxide Synthase|Nitric Oxide Synthase]] | + | *[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Delker, S L]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Li, H]] | + | [[Category: Delker SL]] |
| - | [[Category: Poulos, T L]] | + | [[Category: Li H]] |
| - | [[Category: Heme enzyme]] | + | [[Category: Poulos TL]] |
| - | [[Category: Nitric oxide synthase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Substrate inhibitor]]
| + | |
| - | [[Category: Zn bindings']]
| + | |
| Structural highlights
3n5w is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.73Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
NOS1_RAT Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Inhibitory transmitter for non-adrenergic and non-cholinergic nerves in the colorectum.
Publication Abstract from PubMed
In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martasek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.
Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase .,Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL Biochemistry. 2010 Dec 28;49(51):10803-10. Epub 2010 Dec 7. PMID:21138269[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Delker SL, Xue F, Li H, Jamal J, Silverman RB, Poulos TL. Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase . Biochemistry. 2010 Dec 28;49(51):10803-10. Epub 2010 Dec 7. PMID:21138269 doi:10.1021/bi1013479
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