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| - | [[Image:3nos.jpg|left|200px]]<br /><applet load="3nos" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="3nos, resolution 2.400Å" /> | |
| - | '''HUMAN ENDOTHELIAL NITRIC OXIDE SYNTHASE WITH ARGININE SUBSTRATE'''<br /> | |
| | | | |
| - | ==Overview== | + | ==HUMAN ENDOTHELIAL NITRIC OXIDE SYNTHASE WITH ARGININE SUBSTRATE== |
| - | Crystal structures of human endothelial nitric oxide synthase (eNOS) and, human inducible NOS (iNOS) catalytic domains were solved in complex with, the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger, active-site cavity containing heme and tetrahydrobiopterin. Both are, hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The, active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective, inhibitors. The high-resolution, refined structures of eNOS (2.4 A, resolution) and iNOS (2.25 A resolution) reveal an unexpected structural, zinc situated at the intermolecular interface and coordinated by four, cysteines, two from each monomer. | + | <StructureSection load='3nos' size='340' side='right'caption='[[3nos]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[3nos]] 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=3NOS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NOS 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]] 2.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H4B:5,6,7,8-TETRAHYDROBIOPTERIN'>H4B</scene>, <scene name='pdbligand=HAR:N-OMEGA-HYDROXY-L-ARGININE'>HAR</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=3nos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nos OCA], [https://pdbe.org/3nos PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nos RCSB], [https://www.ebi.ac.uk/pdbsum/3nos PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nos ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [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 == |
| | + | [[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/no/3nos_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=3nos ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 A resolution) and iNOS (2.25 A resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer. |
| | | | |
| - | ==Disease==
| + | Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation.,Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC Nat Struct Biol. 1999 Mar;6(3):233-42. PMID:10074942<ref>PMID:10074942</ref> |
| - | Known diseases associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]], Coronary spasms, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]], Hypertension, pregnancy-induced OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]], Hypertension, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]], Ischemic stroke, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]], Placental abruption OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163729 163729]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 3NOS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HAR:'>HAR</scene>, <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=H4B:'>H4B</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3NOS OCA].
| + | </div> |
| | + | <div class="pdbe-citations 3nos" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation., Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC, Nat Struct Biol. 1999 Mar;6(3):233-42. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10074942 10074942]
| + | *[[Nitric Oxide Synthase|Nitric Oxide Synthase]] |
| | + | *[[Nitric Oxide Synthase 3D structures|Nitric Oxide Synthase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Nitric-oxide synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Single protein]]
| + | [[Category: Fischmann TO]] |
| - | [[Category: Fischmann, T.O.]] | + | [[Category: Weber PC]] |
| - | [[Category: Weber, P.C.]] | + | |
| - | [[Category: H4B]]
| + | |
| - | [[Category: HAR]]
| + | |
| - | [[Category: HEM]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: human]]
| + | |
| - | [[Category: l-arginine monooxygenase]]
| + | |
| - | [[Category: nitric oxide]]
| + | |
| - | [[Category: zns4]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:44:01 2008''
| + | |
| Structural highlights
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.
Publication Abstract from PubMed
Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S-ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 A resolution) and iNOS (2.25 A resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer.
Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation.,Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC Nat Struct Biol. 1999 Mar;6(3):233-42. PMID:10074942[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ Fischmann TO, Hruza A, Niu XD, Fossetta JD, Lunn CA, Dolphin E, Prongay AJ, Reichert P, Lundell DJ, Narula SK, Weber PC. Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation. Nat Struct Biol. 1999 Mar;6(3):233-42. PMID:10074942 doi:http://dx.doi.org/10.1038/6675
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