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 (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 | Comment | Organism | Structure |
---|---|---|---|
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 | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
membrane | neprilysin is a zinc dependent type II integral membrane peptidase | Homo sapiens | 16020 | - |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Zn2+ | neprilysin is a zinc-dependent type II integral membrane peptidase | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
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 | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P08473 | - |
- |
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 | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
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 | 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 | Comment | Organism |
---|---|---|
atriopeptidase | - |
Homo sapiens |
enkephalinase | - |
Homo sapiens |
neutral endopeptidase | - |
Homo sapiens |
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 |