6aur: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
No edit summary
No edit summary
 
(One intermediate revision by the same user not shown)
Line 1: Line 1:


==Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-Fluoro-5-(3-(methylamino)propyl)phenethyl)-4-methylpyridin-2-amine==
==Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-Fluoro-5-(3-(methylamino)propyl)phenethyl)-4-methylpyridin-2-amine==
<StructureSection load='6aur' size='340' side='right' caption='[[6aur]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
<StructureSection load='6aur' size='340' side='right'caption='[[6aur]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6aur]] 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=6AUR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AUR FirstGlance]. <br>
<table><tr><td colspan='2'>[[6aur]] 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=6AUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AUR 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=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=W68:6-(2-{3-fluoro-5-[3-(methylamino)propyl]phenyl}ethyl)-4-methylpyridin-2-amine'>W68</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]] 1.75&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6aut|6aut]], [[6auq|6auq]], [[6aus|6aus]], [[6auz|6auz]], [[6av1|6av1]], [[6auy|6auy]], [[6av0|6av0]], [[6av2|6av2]], [[6av6|6av6]], [[6av7|6av7]], [[6auu|6auu]], [[6auv|6auv]], [[6auw|6auw]], [[6aux|6aux]], [[6av3|6av3]], [[6av4|6av4]], [[6av5|6av5]]</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=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=W68:6-(2-{3-fluoro-5-[3-(methylamino)propyl]phenyl}ethyl)-4-methylpyridin-2-amine'>W68</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, Bnos ([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=6aur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aur OCA], [https://pdbe.org/6aur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6aur RCSB], [https://www.ebi.ac.uk/pdbsum/6aur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6aur 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=6aur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6aur OCA], [http://pdbe.org/6aur PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6aur RCSB], [http://www.ebi.ac.uk/pdbsum/6aur PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6aur 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 ==
Line 23: Line 21:


==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: Li, H]]
[[Category: Rattus norvegicus]]
[[Category: Poulos, T L]]
[[Category: Li H]]
[[Category: Nitric oxide synthase inhibitor complex heme enzyme]]
[[Category: Poulos TL]]
[[Category: Oxidoreductase]]

Latest revision as of 17:25, 4 October 2023

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-Fluoro-5-(3-(methylamino)propyl)phenethyl)-4-methylpyridin-2-amineStructure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-Fluoro-5-(3-(methylamino)propyl)phenethyl)-4-methylpyridin-2-amine

Structural highlights

6aur 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 1.75Å
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

Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively.

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.,Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2017 Nov 22;60(22):9360-9375. doi: 10.1021/acs.jmedchem.7b01356. Epub, 2017 Nov 1. PMID:29091437[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. Do HT, Wang HY, Li H, Chreifi G, Poulos TL, Silverman RB. Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. J Med Chem. 2017 Nov 22;60(22):9360-9375. doi: 10.1021/acs.jmedchem.7b01356. Epub, 2017 Nov 1. PMID:29091437 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01356

6aur, resolution 1.75Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA