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[[Image:1dmt.gif|left|200px]]<br /><applet load="1dmt" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1dmt, resolution 2.1&Aring;" />
'''STRUCTURE OF HUMAN NEUTRAL ENDOPEPTIDASE COMPLEXED WITH PHOSPHORAMIDON'''<br />


==Overview==
==STRUCTURE OF HUMAN NEUTRAL ENDOPEPTIDASE COMPLEXED WITH PHOSPHORAMIDON==
Neutral endopeptidase is a mammalian type II integral membrane zinc-containing endopeptidase, which degrades and inactivates a number of bioactive peptides. The range of substrates cleaved by neutral endopeptidase in vitro includes the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor. Due to the physiological importance of neutral endopeptidase in the modulation of nociceptive and pressor responses there is considerable interest in inhibitors of this enzyme as novel analgesics and anti-hypertensive agents. Here we describe the crystal structure of the extracellular domain (residues 52-749) of human NEP complexed with the generic metalloproteinase inhibitor phosphoramidon at 2.1 A resolution. The structure reveals two multiply connected folding domains which embrace a large central cavity containing the active site. The inhibitor is bound to one side of this cavity and its binding mode provides a detailed understanding of the ligand-binding and specificity determinants.
<StructureSection load='1dmt' size='340' side='right'caption='[[1dmt]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1dmt]] is a 1 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=1DMT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DMT 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=RDF:N-ALPHA-L-RHAMNOPYRANOSYLOXY(HYDROXYPHOSPHINYL)-L-LEUCYL-L-TRYPTOPHAN'>RDF</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=1dmt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dmt OCA], [https://pdbe.org/1dmt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dmt RCSB], [https://www.ebi.ac.uk/pdbsum/1dmt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dmt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NEP_HUMAN NEP_HUMAN] Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.<ref>PMID:2531377</ref> <ref>PMID:15283675</ref> <ref>PMID:20876573</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/dm/1dmt_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=1dmt ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Membranous glomerulonephritis, antenatal OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120520 120520]], Neutral endopeptidase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120520 120520]], Schizophrenia, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=607265 607265]]
*[[Neprilysin|Neprilysin]]
 
== References ==
==About this Structure==
<references/>
1DMT 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=NAG:'>NAG</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=RDF:'>RDF</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Neprilysin Neprilysin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.11 3.4.24.11] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMT OCA].
__TOC__
 
</StructureSection>
==Reference==
Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon., Oefner C, D'Arcy A, Hennig M, Winkler FK, Dale GE, J Mol Biol. 2000 Feb 18;296(2):341-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10669592 10669592]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Neprilysin]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: D'Arcy A]]
[[Category: Arcy, A D.]]
[[Category: Dale GE]]
[[Category: Dale, G E.]]
[[Category: Hennig M]]
[[Category: Hennig, M.]]
[[Category: Oefner C]]
[[Category: Oefner, C.]]
[[Category: Winkler FK]]
[[Category: Winkler, F K.]]
[[Category: GOL]]
[[Category: NAG]]
[[Category: RDF]]
[[Category: ZN]]
[[Category: hydrolase]]
[[Category: metalloprotease]]
[[Category: signal-anchor]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:18:16 2008''

Latest revision as of 16:22, 13 March 2024

STRUCTURE OF HUMAN NEUTRAL ENDOPEPTIDASE COMPLEXED WITH PHOSPHORAMIDONSTRUCTURE OF HUMAN NEUTRAL ENDOPEPTIDASE COMPLEXED WITH PHOSPHORAMIDON

Structural highlights

1dmt is a 1 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 2.1Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NEP_HUMAN Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.[1] [2] [3]

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. ↑ Yandle TG, Brennan SO, Espiner EA, Nicholls MG, Richards AM. Endopeptidase-24.11 in human plasma degrades atrial natriuretic factor (ANF) to ANF(99-105/106-126). Peptides. 1989 Jul-Aug;10(4):891-4. PMID:2531377
  2. ↑ Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004 Oct 1;383(Pt 1):45-51. PMID:15283675 doi:http://dx.doi.org/10.1042/BJ20040634
  3. ↑ Morisaki N, Moriwaki S, Sugiyama-Nakagiri Y, Haketa K, Takema Y, Imokawa G. Neprilysin is identical to skin fibroblast elastase: its role in skin aging and UV responses. J Biol Chem. 2010 Dec 17;285(51):39819-27. doi: 10.1074/jbc.M110.161547. Epub, 2010 Sep 28. PMID:20876573 doi:http://dx.doi.org/10.1074/jbc.M110.161547

1dmt, resolution 2.10Å

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