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5adi

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Revision as of 04:52, 25 May 2023

Structure of human nNOS R354A G357D mutant heme domain in complex with 7-(((5-((Methylamino)methyl)pyridin-3-yl)oxy)methyl)quinolin-2- amine

Structural highlights

5adi 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.
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

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/5adi"

Categories: Homo sapiens | Large Structures | Li H | Poulos TL

@@ Line 3: / Line 3: @@
 <StructureSection load='5adi' size='340' side='right'caption='[[5adi]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5adi]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ADI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ADI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5adi]] 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=5ADI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ADI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=TUE:7-[[5-[(METHYLIDENEAMINO)METHYL]PYRIDIN-3-YL]OXYMETHYL]QUINOLIN-2-AMINE'>TUE</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=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=TUE:7-[[5-[(METHYLIDENEAMINO)METHYL]PYRIDIN-3-YL]OXYMETHYL]QUINOLIN-2-AMINE'>TUE</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]], [[5ad9|5ad9]], [[5ada|5ada]], [[5adb|5adb]], [[5adc|5adc]], [[5add|5add]], [[5ade|5ade]], [[5adf|5adf]], [[5adg|5adg]], [[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=5adi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5adi OCA], [https://pdbe.org/5adi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5adi RCSB], [https://www.ebi.ac.uk/pdbsum/5adi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5adi ProSAT]</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=5adi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5adi OCA], [http://pdbe.org/5adi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5adi RCSB], [http://www.ebi.ac.uk/pdbsum/5adi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5adi ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 20: @@
 ==See Also==
-*[[Nitric Oxide Synthase|Nitric Oxide Synthase]]
+*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Li, H]]
+[[Category: Li H]]
-[[Category: Poulos, T L]]
+[[Category: Poulos TL]]
-[[Category: Nitric oxide synthase]]
-[[Category: Oxidoreductase]]

5adi

From Proteopedia

Revision as of 04:52, 25 May 2023

Structure of human nNOS R354A G357D mutant heme domain in complex with 7-(((5-((Methylamino)methyl)pyridin-3-yl)oxy)methyl)quinolin-2- amine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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