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6sh1

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Crystal structure of substrate-free human neprilysin E584D.

Structural highlights

6sh1 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 2.1Å
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]

Publication Abstract from PubMed

Neprilysin (NEP) is a promiscuous zinc metalloprotease with broad substrate specificity and cleaves a remarkable diversity of substrates through endopeptidase action. Two of these - amyloid-beta and natriuretic peptides - implicate the enzyme in both Alzheimer's disease and cardiovascular disease, respectively. Here, we report the creation of a catalytically inactive NEP (E584D) to determine the first peptide-bound crystal structure at 2.6 A resolution. The structure reveals key interactions involved in substrate binding which we have identified to be conserved in other known zinc metalloproteases. In addition, the structure provides evidence for a potential exosite within the central cavity that may play a critical role in substrate positioning. Together, these results contribute to our understanding of the molecular function of NEP.

Crystal structure of peptide-bound neprilysin reveals key binding interactions.,Moss S, Subramanian V, Acharya KR FEBS Lett. 2020 Jan;594(2):327-336. doi: 10.1002/1873-3468.13602. Epub 2019 Sep, 21. PMID:31514225^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Moss S, Subramanian V, Acharya KR. Crystal structure of peptide-bound neprilysin reveals key binding interactions. FEBS Lett. 2020 Jan;594(2):327-336. doi: 10.1002/1873-3468.13602. Epub 2019 Sep, 21. PMID:31514225 doi:http://dx.doi.org/10.1002/1873-3468.13602