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5ad9

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Revision as of 04:52, 25 May 2023

Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-((4-(Dimethylamino)methyl)phenoxy)methyl)quinolin-2- amine

Structural highlights

5ad9 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.
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

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.,Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martasek P, Poulos TL, Silverman RB J Med Chem. 2015 Nov 12;58(21):8694-712. doi: 10.1021/acs.jmedchem.5b01330. Epub , 2015 Oct 27. PMID:26469213^[1]

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

References

↑ Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martasek P, Poulos TL, Silverman RB. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. J Med Chem. 2015 Nov 12;58(21):8694-712. doi: 10.1021/acs.jmedchem.5b01330. Epub , 2015 Oct 27. PMID:26469213 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01330

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ad9"

Categories: Large Structures | Rattus norvegicus | Li H | Poulos TL

@@ Line 3: / Line 3: @@
 <StructureSection load='5ad9' size='340' side='right'caption='[[5ad9]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ad9]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AD9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AD9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ad9]] 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=5AD9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AD9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8VJ:7-[[4-[(DIMETHYLAMINO)METHYL]PHENOXY]METHYL]QUINOLIN-2-AMINE'>8VJ</scene>, <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=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8VJ:7-[[4-[(DIMETHYLAMINO)METHYL]PHENOXY]METHYL]QUINOLIN-2-AMINE'>8VJ</scene>, <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=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ad4|5ad4]], [[5ad5|5ad5]], [[5ad6|5ad6]], [[5ad7|5ad7]], [[5ad8|5ad8]], [[5ada|5ada]], [[5adb|5adb]], [[5adc|5adc]], [[5add|5add]], [[5ade|5ade]], [[5adf|5adf]], [[5adg|5adg]], [[5adi|5adi]], [[5adj|5adj]], [[5adk|5adk]], [[5adl|5adl]], [[5adm|5adm]], [[5adn|5adn]]</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=5ad9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ad9 OCA], [https://pdbe.org/5ad9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ad9 RCSB], [https://www.ebi.ac.uk/pdbsum/5ad9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ad9 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=5ad9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ad9 OCA], [http://pdbe.org/5ad9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ad9 RCSB], [http://www.ebi.ac.uk/pdbsum/5ad9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ad9 ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 20: @@
 ==See Also==
-*[[Nitric Oxide Synthase|Nitric Oxide Synthase]]
+*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
 == References ==
 <references/>
@@ Line 28: / Line 26: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Li, H]]
+[[Category: Rattus norvegicus]]
-[[Category: Poulos, T L]]
+[[Category: Li H]]
-[[Category: Inhibitor complex]]
+[[Category: Poulos TL]]
-[[Category: Nitric oxide synthase]]
-[[Category: Oxidoreductase]]

5ad9

From Proteopedia

Revision as of 04:52, 25 May 2023

Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-((4-(Dimethylamino)methyl)phenoxy)methyl)quinolin-2- amine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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