View source for 3ufq


==Structure of rat nitric oxide synthase heme domain in complex with 6-(((3S,4S)-4-(((E)-5-(3-fluorophenyl)pent-4-en-1-yl)oxy)pyrrolidin-3-yl)methyl)-4-methylpyridin-2-amine==
<StructureSection load='3ufq' size='340' side='right'caption='[[3ufq]], [[Resolution|resolution]] 2.06&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3ufq]] 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=3UFQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UFQ 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]] 2.058&#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=HW5:6-{[(3S,4S)-4-{[(4E)-5-(3-FLUOROPHENYL)PENT-4-EN-1-YL]OXY}PYRROLIDIN-3-YL]METHYL}-4-METHYLPYRIDIN-2-AMINE'>HW5</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=3ufq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ufq OCA], [https://pdbe.org/3ufq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ufq RCSB], [https://www.ebi.ac.uk/pdbsum/3ufq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ufq 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.
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== Publication Abstract from PubMed ==
The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double-headed pyridine analogs. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability.

Selective Monocationic Inhibitors of Neuronal Nitric Oxide Synthase. Binding Mode Insights from Molecular Dynamics Simulations.,Huang H, Ji H, Li H, Jing Q, Jansen Labby K, Martasek P, Roman LJ, Poulos TL, Silverman RB J Am Chem Soc. 2012 Jun 25. PMID:22731813<ref>PMID:22731813</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3ufq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Li H]]
[[Category: Poulos TL]]