View source for 4cx3


==Structure of rat neuronal nitric oxide synthase M336V D597N mutant heme domain in complex with 4-METHYL-6-(((3R,4R)-4-((5-(PYRIDIN-2-YL) PENTYL)OXY)PYRROLIDIN-3-YL)METHYL)PYRIDIN-2-AMINE==
<StructureSection load='4cx3' size='340' side='right' caption='[[4cx3]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cx3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CX3 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=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=HW8:4-METHYL-6-{[(3R,4R)-4-{[5-(PYRIDIN-2-YL)PENTYL]OXY}PYRROLIDIN-3-YL]METHYL}PYRIDIN-2-AMINE'>HW8</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">[[4cwv|4cwv]], [[4cww|4cww]], [[4cwx|4cwx]], [[4cwy|4cwy]], [[4cwz|4cwz]], [[4cx0|4cx0]], [[4cx1|4cx1]], [[4cx2|4cx2]], [[4cx4|4cx4]], [[4cx5|4cx5]], [[4cx6|4cx6]], [[4cx7|4cx7]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4cx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cx3 OCA], [http://pdbe.org/4cx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cx3 RCSB], [http://www.ebi.ac.uk/pdbsum/4cx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cx3 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. 
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== Publication Abstract from PubMed ==
Many pyrrolidine-based inhibitors highly selective for neuronal nitric oxide synthase (nNOS) over endothelial NOS (eNOS) exhibit dramatically different binding modes. In some cases, the inhibitor binds in a 180 degrees flipped orientation in nNOS relative to eNOS. From the several crystal structures we have determined, we know that isoform selectivity correlates with the rotamer position of a conserved tyrosine residue that H-bonds with a heme propionate. In nNOS, this Tyr more readily adopts the out-rotamer conformation, while in eNOS, the Tyr tends to remain fixed in the original in-rotamer conformation. In the out-rotamer conformation, inhibitors are able to form better H-bonds with the protein and heme, thus increasing inhibitor potency. A segment of polypeptide that runs along the surface near the conserved Tyr has long been thought to be the reason for the difference in Tyr mobility. Although this segment is usually disordered in both eNOS and nNOS, sequence comparisons and modeling from a few structures show that this segment is structured quite differently in eNOS and nNOS. In this study, we have probed the importance of this surface segment near the Tyr by making a few mutants in the region followed by crystal structure determinations. In addition, because the segment near the conserved Tyr is highly ordered in iNOS, we also determined the structure of an iNOS-inhibitor complex. This new structure provides further insight into the critical role that mobility plays in isoform selectivity.

The Mobility of a Conserved Tyrosine Residue Controls Isoform-Dependent Enzyme-Inhibitor Interactions in Nitric Oxide Synthases.,Li H, Jamal J, Delker S, Plaza C, Ji H, Jing Q, Huang H, Kang S, Silverman RB, Poulos TL Biochemistry. 2014 Aug 11. PMID:25089924<ref>PMID:25089924</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 4cx3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Li, H]]
[[Category: Poulos, T L]]
[[Category: Inhibitor complex]]
[[Category: Oxidoreductase]]