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6po5

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Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(3-(Aminomethyl)-4-(cyclobutylmethoxy)phenyl)-4-methylquinolin-2-amine

Structural highlights

6po5 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 1.82Å
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

Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a meta-relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.

First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.,Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2020 Apr 17. doi: 10.1021/acs.jmedchem.9b01573. PMID:32302123^[1]

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

References

↑ Cinelli MA, Reidl CT, Li H, Chreifi G, Poulos TL, Silverman RB. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. J Med Chem. 2020 Apr 17. doi: 10.1021/acs.jmedchem.9b01573. PMID:32302123 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01573

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/6po5"

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

@@ Line 3: / Line 3: @@
 <StructureSection load='6po5' size='340' side='right'caption='[[6po5]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6po5]] 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=6PO5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6PO5 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6po5]] 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=6PO5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PO5 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=OUP:7-[3-(aminomethyl)-4-(cyclobutylmethoxy)phenyl]-4-methylquinolin-2-amine'>OUP</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]] 1.82&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=OUP:7-[3-(aminomethyl)-4-(cyclobutylmethoxy)phenyl]-4-methylquinolin-2-amine'>OUP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6po5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6po5 OCA], [https://pdbe.org/6po5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6po5 RCSB], [https://www.ebi.ac.uk/pdbsum/6po5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6po5 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6po5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6po5 OCA], [http://pdbe.org/6po5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6po5 RCSB], [http://www.ebi.ac.uk/pdbsum/6po5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6po5 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 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6po5" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Li, H]]
+[[Category: Li H]]
-[[Category: Poulos, T L]]
+[[Category: Poulos TL]]
-[[Category: Nitric oxide synthase inhibitor complex heme enzyme]]
-[[Category: Oxidoreductase]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

6po5

From Proteopedia

Current revision

Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(3-(Aminomethyl)-4-(cyclobutylmethoxy)phenyl)-4-methylquinolin-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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