|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5uo5' size='340' side='right'caption='[[5uo5]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='5uo5' size='340' side='right'caption='[[5uo5]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5uo5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UO5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UO5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5uo5]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UO5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UO5 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8FD:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2S)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>8FD</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=M4R:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2R)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>M4R</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5unr|5unr]], [[5unu|5unu]], [[5unx|5unx]], [[5unw|5unw]], [[5uo1|5uo1]], [[5uny|5uny]], [[5uo3|5uo3]], [[5uo4|5uo4]], [[5uo6|5uo6]], [[5uo7|5uo7]], [[5uo8|5uo8]], [[5uo2|5uo2]], [[5uns|5uns]], [[5unz|5unz]], [[5uo0|5uo0]], [[5unt|5unt]], [[5unv|5unv]], [[5uod|5uod]], [[5uo9|5uo9]], [[5uoa|5uoa]], [[5uob|5uob]], [[5uoc|5uoc]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8FD:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2S)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>8FD</scene>, <scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=M4R:3-[(2-AMINO-4-METHYLQUINOLIN-7-YL)METHOXY]-5-[(2R)-2-(METHYLAMINO)PROPYL]BENZONITRILE'>M4R</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">NOS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5uo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uo5 OCA], [https://pdbe.org/5uo5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uo5 RCSB], [https://www.ebi.ac.uk/pdbsum/5uo5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uo5 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=5uo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uo5 OCA], [http://pdbe.org/5uo5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uo5 RCSB], [http://www.ebi.ac.uk/pdbsum/5uo5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uo5 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NOS1_HUMAN NOS1_HUMAN]] 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. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. | + | [https://www.uniprot.org/uniprot/NOS1_HUMAN NOS1_HUMAN] 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. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 28: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Li, H]] | + | [[Category: Li H]] |
| - | [[Category: Poulos, T L]] | + | [[Category: Poulos TL]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Enzyme]]
| + | |
| - | [[Category: Heme]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Nitric]]
| + | |
| - | [[Category: Oxide]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Synthase]]
| + | |
| Structural highlights
5uo5 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
NOS1_HUMAN 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. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
Publication Abstract from PubMed
Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high ( approximately 500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds.
Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.,Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2017 Apr 19. doi: 10.1021/acs.jmedchem.7b00259. PMID:28422508[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. J Med Chem. 2017 Apr 19. doi: 10.1021/acs.jmedchem.7b00259. PMID:28422508 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00259
|
