2hx3: Difference between revisions

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[[Image:2hx3.gif|left|200px]]
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{{STRUCTURE_2hx3|  PDB=2hx3  |  SCENE=  }}
'''Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine'''


==Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine==
<StructureSection load='2hx3' size='340' side='right'caption='[[2hx3]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2hx3]] 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=2HX3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HX3 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&#8491;</td></tr>
<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=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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hx3 OCA], [https://pdbe.org/2hx3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hx3 RCSB], [https://www.ebi.ac.uk/pdbsum/2hx3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hx3 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.
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hx/2hx3_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2hx3 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


==Overview==
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:17425297<ref>PMID:17425297</ref>
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.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2HX3 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HX3 OCA].
</div>
<div class="pdbe-citations 2hx3" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
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]
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
[[Category: Nitric-oxide synthase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
[[Category: Single protein]]
[[Category: Igarashi J]]
[[Category: Igarashi, J.]]
[[Category: Li H]]
[[Category: Li, H.]]
[[Category: Poulos TL]]
[[Category: Poulos, T L.]]
[[Category: Heme enzyme]]
[[Category: Inhibitor]]
[[Category: Nitric oxide synthase]]
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