3eah: Difference between revisions

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==Structure of inhibited human eNOS oxygenase domain==
==Structure of inhibited human eNOS oxygenase domain==
<StructureSection load='3eah' size='340' side='right' caption='[[3eah]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
<StructureSection load='3eah' size='340' side='right'caption='[[3eah]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3eah]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EAH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EAH FirstGlance]. <br>
<table><tr><td colspan='2'>[[3eah]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EAH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EAH FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=327:(3S,5E)-3-PROPYL-3,4-DIHYDROTHIENO[2,3-F][1,4]OXAZEPIN-5(2H)-IMINE'>327</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><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]] 2.44&#8491;</td></tr>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3e65|3e65]], [[3e67|3e67]], [[3e68|3e68]], [[3e6l|3e6l]], [[3e6n|3e6n]], [[3e6o|3e6o]], [[3e6t|3e6t]], [[3e7g|3e7g]], [[3e7i|3e7i]], [[3e7m|3e7m]], [[3e7s|3e7s]], [[3e7t|3e7t]], [[3eai|3eai]], [[3ebd|3ebd]], [[3ebf|3ebf]], [[3ej8|3ej8]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=327:(3S,5E)-3-PROPYL-3,4-DIHYDROTHIENO[2,3-F][1,4]OXAZEPIN-5(2H)-IMINE'>327</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Nos3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3eah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eah OCA], [https://pdbe.org/3eah PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3eah RCSB], [https://www.ebi.ac.uk/pdbsum/3eah PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3eah ProSAT]</span></td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
</table>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3eah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eah OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3eah RCSB], [http://www.ebi.ac.uk/pdbsum/3eah PDBsum]</span></td></tr>
== Function ==
<table>
[https://www.uniprot.org/uniprot/NOS3_HUMAN NOS3_HUMAN] 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.<ref>PMID:17264164</ref>  Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.<ref>PMID:17264164</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ea/3eah_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ea/3eah_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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/chain_selection.php?pdb_ID=2ata ConSurf].
</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=3eah ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.,Garcin ED, Arvai AS, Rosenfeld RJ, Kroeger MD, Crane BR, Andersson G, Andrews G, Hamley PJ, Mallinder PR, Nicholls DJ, St-Gallay SA, Tinker AC, Gensmantel NP, Mete A, Cheshire DR, Connolly S, Stuehr DJ, Aberg A, Wallace AV, Tainer JA, Getzoff ED Nat Chem Biol. 2008 Nov;4(11):700-7. Epub 2008 Oct 12. PMID:18849972<ref>PMID:18849972</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Nitric Oxide Synthase|Nitric Oxide Synthase]]
*[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Nitric-oxide synthase]]
[[Category: Large Structures]]
[[Category: Aberg, A.]]
[[Category: Aberg A]]
[[Category: Andersson, G.]]
[[Category: Andersson G]]
[[Category: Andrews, G.]]
[[Category: Andrews G]]
[[Category: Arvai, A S.]]
[[Category: Arvai AS]]
[[Category: Cheshire, D R.]]
[[Category: Cheshire DR]]
[[Category: Connolly, S.]]
[[Category: Connolly S]]
[[Category: Crane, B R.]]
[[Category: Crane BR]]
[[Category: Garcin, E D.]]
[[Category: Garcin ED]]
[[Category: Gensmantel, N P.]]
[[Category: Gensmantel NP]]
[[Category: Getzoff, E D.]]
[[Category: Getzoff ED]]
[[Category: Hamley, P J.]]
[[Category: Hamley PJ]]
[[Category: Kroeger, M D.]]
[[Category: Kroeger MD]]
[[Category: Mallinder, P R.]]
[[Category: Mallinder PR]]
[[Category: Mete, A.]]
[[Category: Mete A]]
[[Category: Nicholls, D J.]]
[[Category: Nicholls DJ]]
[[Category: Rosenfeld, R J.]]
[[Category: Rosenfeld RJ]]
[[Category: St-Gallay, S A.]]
[[Category: St-Gallay SA]]
[[Category: Stuehr, D J.]]
[[Category: Stuehr DJ]]
[[Category: Tainer, J A.]]
[[Category: Tainer JA]]
[[Category: Tinker, A C.]]
[[Category: Tinker AC]]
[[Category: Wallace, A V.]]
[[Category: Wallace AV]]
[[Category: Fad]]
[[Category: Fmn]]
[[Category: Heme]]
[[Category: Iron]]
[[Category: Metal-binding]]
[[Category: Nadp]]
[[Category: Nitric oxide synthase]]
[[Category: No]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase calmodulin-binding]]
[[Category: Tetrahydrobiopterin]]

Latest revision as of 12:46, 21 February 2024

Structure of inhibited human eNOS oxygenase domainStructure of inhibited human eNOS oxygenase domain

Structural highlights

3eah is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.44Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NOS3_HUMAN 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.[1] Isoform eNOS13C: Lacks eNOS activity, dominant-negative form that may down-regulate eNOS activity by forming heterodimers with isoform 1.[2]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Lorenz M, Hewing B, Hui J, Zepp A, Baumann G, Bindereif A, Stangl V, Stangl K. Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity. FASEB J. 2007 May;21(7):1556-64. Epub 2007 Jan 30. PMID:17264164 doi:http://dx.doi.org/10.1096/fj.06-7434com
  2. ↑ Lorenz M, Hewing B, Hui J, Zepp A, Baumann G, Bindereif A, Stangl V, Stangl K. Alternative splicing in intron 13 of the human eNOS gene: a potential mechanism for regulating eNOS activity. FASEB J. 2007 May;21(7):1556-64. Epub 2007 Jan 30. PMID:17264164 doi:http://dx.doi.org/10.1096/fj.06-7434com

3eah, resolution 2.44Å

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