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6ngn

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Current revision

Structure of rat neuronal nitric oxide synthase heme domain in complex with (S)-6-(3-fluoro-5-(2-(pyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-2-amine

Structural highlights

6ngn 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 1.9Å
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

Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the p Ka of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency ( Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.

Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.,Do HT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056^[1]

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

References

↑ Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b02032

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/6ngn"

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

@@ Line 3: / Line 3: @@
 <StructureSection load='6ngn' size='340' side='right'caption='[[6ngn]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ngn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NGN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NGN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ngn]] 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=6NGN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NGN 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=KL4:6-[2-(3-fluoro-5-{2-[(2S)-pyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine'>KL4</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]] 1.9&#8491;</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='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=KL4:6-[2-(3-fluoro-5-{2-[(2S)-pyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine'>KL4</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ngn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ngn OCA], [http://pdbe.org/6ngn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ngn RCSB], [http://www.ebi.ac.uk/pdbsum/6ngn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ngn ProSAT]</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=6ngn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ngn OCA], [https://pdbe.org/6ngn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ngn RCSB], [https://www.ebi.ac.uk/pdbsum/6ngn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ngn 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 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6ngn" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[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]]
-[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

6ngn

From Proteopedia

Current revision

Structure of rat neuronal nitric oxide synthase heme domain in complex with (S)-6-(3-fluoro-5-(2-(pyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-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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