6suk | pdb_00006suk

Crystal structure of Neprilysin in complex with Omapatrilat.

spinqualitylabelsall models 6suk, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6suk is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, FT8, NAG, PEG, ZN Related: 6gid Gene: MME, EPN (HUMAN) Activity: Neprilysin, with EC number 3.4.24.11 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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