Literature summary for 3.4.24.11 extracted from

Schiering, N.; DArcy, A.; Villard, F.; Ramage, P.; Logel, C.; Cumin, F.; Ksander, G.M.; Wiesmann, C.; Karki, R.G.; Mogi, M.
Structure of neprilysin in complex with the active metabolite of sacubitril (2016), Sci. Rep., 6, 27909 .

Search for more literature for 3.4.24.11

Cloned(Commentary)

Cloned (Comment)	Organism
recombinant expression of C-terminally Strep-tagged neprilysin residues Gly52-Trp749 with a cathepsin D leader sequence, comprising the extracellular domain of NEP, in Spodoptera frugiperda cells using the baculovirus transfection system	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
purified recombinant extracellular domain of human NEP (residues 54-749) in complex with LBQ657, hanging drop vapor diffusion method, mixing of 10 mg/ml protein in 20 mM Tris, pH 8.0, 125 mM NaCl, 2 mM MgCl2 and 1 mM in a 1:1 ratio with reservoir solution containing 25% w/v PEG 3350, 200 mM ammonium acetate, and 100 mM BisTris, pH 6.5, room temperature, overnight, X-ray diffraction structure determination and analysis at 2.0 A resolution, molecular replacement	Homo sapiens

Crystallization (Comment)

Organism

purified recombinant extracellular domain of human NEP (residues 54-749) in complex with LBQ657, hanging drop vapor diffusion method, mixing of 10 mg/ml protein in 20 mM Tris, pH 8.0, 125 mM NaCl, 2 mM MgCl2 and 1 mM in a 1:1 ratio with reservoir solution containing 25% w/v PEG 3350, 200 mM ammonium acetate, and 100 mM BisTris, pH 6.5, room temperature, overnight, X-ray diffraction structure determination and analysis at 2.0 A resolution, molecular replacement

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
sacubitril	-	Homo sapiens
sacubitrilat	LBQ657, the inhibitor is bound to the active site of NEP by an intricate network of interactions that involves all functional groups of the compound giving rise to the high inhibitory potency. The catalytic zinc atom of NEP is ligated by the side chains of residues His583, His587, and Glu646 with the fourth coordination provided by the carboxylate oxygen adjacent to the P1 methyl of the compound, the backbone amide of LBQ657 forms H-bonding interactions with the side chains of Asn542 and Arg717. Enzyme active site binding structure, interaction, and inhibition mechanism, modelling, overview. All of the molecular interactions between LBQ657 and the enzyme are noncovalent, in line with a reversible inhibition mode	Homo sapiens
valsartan	-	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
membrane	neprilysin is a zinc dependent type II integral membrane peptidase	Homo sapiens	16020	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Zn2+	neprilysin is a zinc-dependent type II integral membrane peptidase	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
adrenomedullin + H2O	Homo sapiens	-	?	-	?
atrial natriuretic peptide + H2O	Homo sapiens	-	?	-	?
bradykinin + H2O	Homo sapiens	-	?	-	?
brain natriuretic peptide + H2O	Homo sapiens	-	?	-	?
endothelin-1 + H2O	Homo sapiens	-	?	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	P08473	-	-

Purification (Commentary)

Purification (Comment)	Organism
recombinant C-terminally Strep-tagged neprilysin residues Gly52-Trp749 from Spodoptera frugiperda cells by concanavalin A affinity chromatography, dialysis, ammonium sulfate fractionation, hydrophobic interaction chromatography, anion exchange chromatography, and ultrafiltration	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
adrenomedullin + H2O	-	Homo sapiens	?	-	?
atrial natriuretic peptide + H2O	-	Homo sapiens	?	-	?
bradykinin + H2O	-	Homo sapiens	?	-	?
brain natriuretic peptide + H2O	-	Homo sapiens	?	-	?
endothelin-1 + H2O	-	Homo sapiens	?	-	?

Subunits

Subunits	Comment	Organism
More	the extracellular domain of NEP is comprised of two largely alpha-helical subdomains, with domain 1 predominantly containing C-terminal residues while domain 2 is formed mainly from the N-terminal half of the protein. The two domains are arranged to harbor a large cavity in the center that contains the catalytic machinery which is formed by residues from domain	Homo sapiens

Synonyms

Synonyms	Comment	Organism
atriopeptidase	-	Homo sapiens
enkephalinase	-	Homo sapiens
neutral endopeptidase	-	Homo sapiens

General Information

General Information	Comment	Organism
evolution	neprilysin is a zinc dependent type II integral membrane peptidase belonging to the M13 family	Homo sapiens
malfunction	NEP inhibition leads to an increased level of vasoactive peptides such as atrial natriuretic peptide, brain natriuretic peptide, bradykinin, adrenomedullin, and endothelin-1. The combination of NEP and angiotensin receptor inhibition is superior to either agent alone and leads to vasodilation and reduction of extracellular fluid via sodium excretion	Homo sapiens
additional information	selectivity of the compound LBQ657 for NEP relative to the homologous peptidases, endothelin converting enzyme (ECE-1) and neprilysin 2 (NEP2)	Homo sapiens
physiological function	neprilysin degrades a variety of vasoactive peptides such as atrial natriuretic peptide, brain natriuretic peptide, bradykinin, adrenomedullin, and endothelin-1	Homo sapiens