6pn2: Difference between revisions

Latest revision as of 13:43, 13 August 2026

Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-isopropoxyphenyl)-4-methylquinolin-2-amine

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.877Å
Ligands:	ACT, H4B, HEM, OSD, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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:https://dx.doi.org/10.1021/acs.jmedchem.9b01573

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OCA

[1] 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:https://dx.doi.org/10.1021/acs.jmedchem.9b01573

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='6pn2' size='340' side='right'caption='[[6pn2]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pn2]] 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=6PN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PN2 FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PN2 FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.877&#8491;</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=OSD:7-{3-(aminomethyl)-4-[(propan-2-yl)oxy]phenyl}-4-methylquinolin-2-amine'>OSD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6pn2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pn2 OCA], [https://pdbe.org/6pn2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pn2 RCSB], [https://www.ebi.ac.uk/pdbsum/6pn2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pn2 ProSAT]</span></td></tr>
 </table>
-== Function ==
-[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 27: / Line 25: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Rattus norvegicus]]
 [[Category: Li H]]
 [[Category: Poulos TL]]

6pn2: Difference between revisions

Latest revision as of 13:43, 13 August 2026

Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-isopropoxyphenyl)-4-methylquinolin-2-amine

Structural highlights

Publication Abstract from PubMed

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References

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