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| - | ==CRYSTAL STRUCTURE OF HUMAN NEUTRAL ENDOPEPTIDASE COMPLEXED WITH A HETEROARYLALANINE DIACID.== | + | ==Crystal Structure of Human Neutral Endopeptidase complexed with a heteroarylalanine diacid.== |
| - | <StructureSection load='2yb9' size='340' side='right' caption='[[2yb9]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='2yb9' size='340' side='right'caption='[[2yb9]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2yb9]] 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=2YB9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YB9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2yb9]] 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=2YB9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YB9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HA0:HETEROARYLALANINE+5-PHENYL+OXAZOLE'>HA0</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qvd|1qvd]], [[1y8j|1y8j]], [[1r1j|1r1j]], [[1dl9|1dl9]], [[1r1h|1r1h]], [[1dmt|1dmt]], [[1r1i|1r1i]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HA0:HETEROARYLALANINE+5-PHENYL+OXAZOLE'>HA0</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=2yb9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yb9 OCA], [https://pdbe.org/2yb9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yb9 RCSB], [https://www.ebi.ac.uk/pdbsum/2yb9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yb9 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2yb9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yb9 OCA], [http://pdbe.org/2yb9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yb9 RCSB], [http://www.ebi.ac.uk/pdbsum/2yb9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yb9 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Neprilysin]] | + | [[Category: Large Structures]] |
| - | [[Category: Bazin, R J]] | + | [[Category: Bazin RJ]] |
| - | [[Category: Dack, K N]] | + | [[Category: Dack KN]] |
| - | [[Category: Done, S]] | + | [[Category: Done S]] |
| - | [[Category: Fox, D N.A]] | + | [[Category: Fox DNA]] |
| - | [[Category: Glossop, M S]] | + | [[Category: Glossop MS]] |
| - | [[Category: Macdonald, G A]] | + | [[Category: MacDonald GA]] |
| - | [[Category: Mills, M]] | + | [[Category: Mills M]] |
| - | [[Category: Owen, D R]] | + | [[Category: Owen DR]] |
| - | [[Category: Phillips, C]] | + | [[Category: Phillips C]] |
| - | [[Category: Reeves, K A]] | + | [[Category: Reeves KA]] |
| - | [[Category: Ringer, T J]] | + | [[Category: Ringer TJ]] |
| - | [[Category: Strang, R S]] | + | [[Category: Strang RS]] |
| - | [[Category: Watson, C A.L]] | + | [[Category: Watson CAL]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Metalloproteinase]]
| + | |
| - | [[Category: Neprilysine]]
| + | |
| 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
Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.
Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors.,Glossop MS, Bazin RJ, Dack KN, Fox DN, Macdonald GA, Mills M, Owen DR, Phillips C, Reeves KA, Ringer TJ, Strang RS, Watson CA Bioorg Med Chem Lett. 2011 Jun 1;21(11):3404-6. Epub 2011 Apr 5. PMID:21515054[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
- ↑ Glossop MS, Bazin RJ, Dack KN, Fox DN, Macdonald GA, Mills M, Owen DR, Phillips C, Reeves KA, Ringer TJ, Strang RS, Watson CA. Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3404-6. Epub 2011 Apr 5. PMID:21515054 doi:10.1016/j.bmcl.2011.03.109
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