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| | <StructureSection load='6xvp' size='340' side='right'caption='[[6xvp]], [[Resolution|resolution]] 2.65Å' scene=''> | | <StructureSection load='6xvp' size='340' side='right'caption='[[6xvp]], [[Resolution|resolution]] 2.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6xvp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XVP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XVP FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6xvp]] 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=6XVP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XVP FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D0Z:Sampatrilat'>D0Z</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MME, EPN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D0Z:Sampatrilat'>D0Z</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></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=6xvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xvp OCA], [https://pdbe.org/6xvp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xvp RCSB], [https://www.ebi.ac.uk/pdbsum/6xvp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xvp ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6xvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xvp OCA], [http://pdbe.org/6xvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xvp RCSB], [http://www.ebi.ac.uk/pdbsum/6xvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xvp ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6xvp" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6xvp" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Neprilysin|Neprilysin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Neprilysin]]
| + | [[Category: Acharya KR]] |
| - | [[Category: Acharya, K R]] | + | [[Category: Cozier GE]] |
| - | [[Category: Cozier, G E]] | + | [[Category: Sharma U]] |
| - | [[Category: Sharma, U]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Metallopeptidase]]
| + | |
| - | [[Category: Neural endopeptidase]]
| + | |
| - | [[Category: Sampatrilat]]
| + | |
| Structural highlights
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]
Publication Abstract from PubMed
Neprilysin (NEP) and angiotensin-converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependent conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependent degradation of vasodilator atrial natriuretic peptide. Here, we report crystal structures of omapatrilat, sampatrilat, and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75, 2.65, and 2.6 A, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.
Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme.,Sharma U, Cozier GE, Sturrock ED, Acharya KR J Med Chem. 2020 May 8. doi: 10.1021/acs.jmedchem.0c00441. PMID:32337993[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Sharma U, Cozier GE, Sturrock ED, Acharya KR. Molecular Basis for Omapatrilat and Sampatrilat Binding to Neprilysin-Implications for Dual Inhibitor Design with Angiotensin-Converting Enzyme. J Med Chem. 2020 May 8. doi: 10.1021/acs.jmedchem.0c00441. PMID:32337993 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00441
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