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PDBsum entry 1dmt
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon.
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Authors
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C.Oefner,
A.D'Arcy,
M.Hennig,
F.K.Winkler,
G.E.Dale.
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Ref.
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J Mol Biol, 2000,
296,
341-349.
[DOI no: ]
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PubMed id
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Abstract
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Neutral endopeptidase is a mammalian type II integral membrane zinc-containing
endopeptidase, which degrades and inactivates a number of bioactive peptides.
The range of substrates cleaved by neutral endopeptidase in vitro includes the
enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor.
Due to the physiological importance of neutral endopeptidase in the modulation
of nociceptive and pressor responses there is considerable interest in
inhibitors of this enzyme as novel analgesics and anti-hypertensive agents. Here
we describe the crystal structure of the extracellular domain (residues 52-749)
of human NEP complexed with the generic metalloproteinase inhibitor
phosphoramidon at 2.1 A resolution. The structure reveals two multiply connected
folding domains which embrace a large central cavity containing the active site.
The inhibitor is bound to one side of this cavity and its binding mode provides
a detailed understanding of the ligand-binding and specificity determinants.
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Figure 4.
Figure 4. Ribbon plot of sNEP depicting the volume of the
active site cavity.
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Figure 5.
Figure 5. Inhibitor binding to the active site of human
sNEP. (a) Stereo view of the active site inhibited by
phosphoramidon, green. Hydrogen bonds and ionic interactions are
indicated by broken lines, a-helices are shown as cylinders,
b-strands are represented by arrows: catalytic domain, violet;
the smaller domain 2, blue; the three interdomain linker
fragments, cyan. The zinc ion is shown in yellow. (b) Molecular
surface of the phosphoramidon recognition site colored by
electrostatic potential: positive, blue; negative, red.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2000,
296,
341-349)
copyright 2000.
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