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2hx2

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[[Image:2hx2.gif|left|200px]]
 
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{{Structure
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==Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine==
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|PDB= 2hx2 |SIZE=350|CAPTION= <scene name='initialview01'>2hx2</scene>, resolution 1.95&Aring;
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<StructureSection load='2hx2' size='340' side='right'caption='[[2hx2]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=BH4:(6R,1&#39;R,2&#39;S)-5,6,7,8+TETRAHYDROBIOPTERIN'>BH4</scene>, <scene name='pdbligand=3HX:(4S)-N-{4-AMINO-5-[(2-AMINOETHYL)(HYDROXYAMINO]-PENTYL}-N&#39;-NITROGUANIDINE'>3HX</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
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<table><tr><td colspan='2'>[[2hx2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HX2 FirstGlance]. <br>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39]
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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|GENE= NOS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 Bos taurus])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3HX:(4S)-N-{4-AMINO-5-[(2-AMINOETHYL)(HYDROXYAMINO]-PENTYL}-N-NITROGUANIDINE'>3HX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</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=ZN:ZINC+ION'>ZN</scene></td></tr>
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}}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hx2 OCA], [https://pdbe.org/2hx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hx2 RCSB], [https://www.ebi.ac.uk/pdbsum/2hx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hx2 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/NOS3_BOVIN NOS3_BOVIN] Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hx/2hx2_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2hx2 ConSurf].
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<div style="clear:both"></div>
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'''Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine'''
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==See Also==
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*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
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__TOC__
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==Overview==
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</StructureSection>
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The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to the discovery of a conserved structural water molecule that was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of 2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water molecule and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogues 3-5, which have either an N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors 3 and 5 bound verified that the N-hydroxyl group had, indeed, displaced the structural water molecule and provided a direct interaction with the heme propionate moiety (Figures 5 and 6). Surprisingly, in vitro activity assay results indicated that the addition of a hydroxyl group (3) only increased the potency slightly against the neuronal isoform over the parent compound (1). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.
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==About this Structure==
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2HX2 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HX2 OCA].
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==Reference==
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Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water., Seo J, Igarashi J, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB, J Med Chem. 2007 May 3;50(9):2089-99. Epub 2007 Apr 11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17425297 17425297]
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[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Nitric-oxide synthase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Igarashi J]]
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[[Category: Igarashi, J.]]
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[[Category: Li H]]
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[[Category: Li, H.]]
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[[Category: Poulos TL]]
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[[Category: Poulos, T L.]]
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[[Category: 3HX]]
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[[Category: ACT]]
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[[Category: BH4]]
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[[Category: CAC]]
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[[Category: GOL]]
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[[Category: HEM]]
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[[Category: ZN]]
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[[Category: heme enzyme]]
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[[Category: inhibitor]]
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[[Category: nitric oxide synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 15:17:51 2008''
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Current revision

Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine

PDB ID 2hx2

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