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PDBsum entry 1dmt
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.24.11
- neprilysin.
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Reaction:
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Preferential cleavage at the amino group of hydrophobic residues in insulin, casein, hemoglobin, and a number of other proteins and polypeptides.
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Cofactor:
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Zn(2+)
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DOI no:
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J Mol Biol
296:341-349
(2000)
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PubMed id:
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Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon.
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C.Oefner,
A.D'Arcy,
M.Hennig,
F.K.Winkler,
G.E.Dale.
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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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Selected figure(s)
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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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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Ruf,
M.Stihle,
J.Benz,
M.Schmidt,
and
H.Sobek
(2013).
Structure of Gentlyase, the neutral metalloprotease of Paenibacillus polymyxa.
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Acta Crystallogr D Biol Crystallogr,
69,
24-31.
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PDB codes:
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N.M.Burton,
and
G.Daniels
(2011).
Structural modelling of red cell surface proteins.
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Vox Sang,
100,
129-139.
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V.Maguer-Satta,
R.Besançon,
and
E.Bachelard-Cascales
(2011).
Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer.
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Stem Cells,
29,
389-396.
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G.A.Dalkas,
A.Papakyriakou,
A.Vlamis-Gardikas,
and
G.A.Spyroulias
(2009).
Insights into the anthrax lethal factor-substrate interaction and selectivity using docking and molecular dynamics simulations.
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Protein Sci,
18,
1774-1785.
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E.Malito,
R.E.Hulse,
and
W.J.Tang
(2008).
Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin.
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Cell Mol Life Sci,
65,
2574-2585.
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G.D.Van Vickle,
C.L.Esh,
T.A.Kokjohn,
R.L.Patton,
W.M.Kalback,
D.C.Luehrs,
T.G.Beach,
A.J.Newel,
F.Lopera,
B.Ghetti,
R.Vidal,
E.M.Castaño,
and
A.E.Roher
(2008).
Presenilin-1 280Glu-->Ala mutation alters C-terminal APP processing yielding longer abeta peptides: implications for Alzheimer's disease.
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Mol Med,
14,
184-194.
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K.Gagnidze,
Sachchidanand,
R.Rozenfeld,
M.Mezei,
M.M.Zhou,
and
L.A.Devi
(2008).
Homology modeling and site-directed mutagenesis to identify selective inhibitors of endothelin-converting enzyme-2.
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J Med Chem,
51,
3378-3387.
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N.D.Bland,
J.W.Pinney,
J.E.Thomas,
A.J.Turner,
and
R.E.Isaac
(2008).
Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships.
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BMC Evol Biol,
8,
16.
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P.K.Baral,
N.Jajcanin-Jozić,
S.Deller,
P.Macheroux,
M.Abramić,
and
K.Gruber
(2008).
The first structure of dipeptidyl-peptidase III provides insight into the catalytic mechanism and mode of substrate binding.
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J Biol Chem,
283,
22316-22324.
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PDB code:
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R.E.Llovera,
M.de Tullio,
L.G.Alonso,
M.A.Leissring,
S.B.Kaufman,
A.E.Roher,
G.de Prat Gay,
L.Morelli,
and
E.M.Castaño
(2008).
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide: implications for Alzheimer disease pathogenesis.
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J Biol Chem,
283,
17039-17048.
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W.N.Addison,
Y.Nakano,
T.Loisel,
P.Crine,
and
M.D.McKee
(2008).
MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM.
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J Bone Miner Res,
23,
1638-1649.
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B.M.McArdle,
and
R.J.Quinn
(2007).
Identification of protein fold topology shared between different folds inhibited by natural products.
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Chembiochem,
8,
788-798.
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C.Oefner,
S.Pierau,
H.Schulz,
and
G.E.Dale
(2007).
Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV.
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Acta Crystallogr D Biol Crystallogr,
63,
975-981.
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PDB code:
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E.J.Lim,
S.Sampath,
J.Coll-Rodriguez,
J.Schmidt,
K.Ray,
and
D.W.Rodgers
(2007).
Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase.
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J Biol Chem,
282,
9722-9732.
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PDB codes:
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N.M.Barros,
M.Campos,
P.A.Bersanetti,
V.Oliveira,
M.A.Juliano,
G.Boileau,
L.Juliano,
and
A.K.Carmona
(2007).
Neprilysin carboxydipeptidase specificity studies and improvement in its detection with fluorescence energy transfer peptides.
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Biol Chem,
388,
447-455.
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P.Daull,
A.Y.Jeng,
and
B.Battistini
(2007).
Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases.
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J Cardiovasc Pharmacol,
50,
247-256.
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G.N.Maw,
A.Stobie,
S.Planken,
D.C.Pryde,
V.Sanderson,
M.Y.Platts,
M.Corless,
P.Stacey,
C.Wayman,
P.Van Der Graaf,
C.Kohl,
S.Coggon,
and
K.Beaumont
(2006).
The discovery of small molecule inhibitors of neutral endopeptidase. Structure-activity studies on functionalized glutaramides.
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Chem Biol Drug Des,
67,
74-77.
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S.Lee,
A.K.Debnath,
X.Wu,
T.Scofield,
T.George,
R.Kakaiya,
M.G.Yogore,
L.Sausais,
M.Yacob,
C.Lomas-Francis,
and
M.E.Reid
(2006).
Molecular basis of two novel high-prevalence antigens in the Kell blood group system, KALT and KTIM.
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Transfusion,
46,
1323-1327.
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A.Clapéron,
C.Rose,
P.Gane,
E.Collec,
O.Bertrand,
and
T.Ouimet
(2005).
The Kell protein of the common K2 phenotype is a catalytically active metalloprotease, whereas the rare Kell K1 antigen is inactive. Identification of novel substrates for the Kell protein.
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J Biol Chem,
280,
21272-21283.
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N.Iwata,
M.Higuchi,
and
T.C.Saido
(2005).
Metabolism of amyloid-beta peptide and Alzheimer's disease.
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Pharmacol Ther,
108,
129-148.
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C.Oefner,
B.P.Roques,
M.C.Fournie-Zaluski,
and
G.E.Dale
(2004).
Structural analysis of neprilysin with various specific and potent inhibitors.
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Acta Crystallogr D Biol Crystallogr,
60,
392-396.
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PDB codes:
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N.Inguimbert,
H.Poras,
H.Dhotel,
F.Beslot,
E.Scalbert,
C.Bennejean,
P.Renard,
M.C.Fournié-Zaluski,
and
B.P.Roques
(2004).
In vivo properties of thiol inhibitors of the three vasopeptidases NEP, ACE and ECE are improved by introduction of a 7-azatryptophan in P2' position.
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J Pept Res,
63,
99.
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S.Sahli,
B.Stump,
T.Welti,
D.Blum-Kaelin,
J.D.Aebi,
C.Oefner,
H.J.Böhm,
and
F.Diederich
(2004).
Structure-based design, synthesis, and in vitro evaluation of nonpeptidic neprilysin inhibitors.
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Chembiochem,
5,
996.
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S.Voisin,
D.Rognan,
C.Gros,
and
T.Ouimet
(2004).
A three-dimensional model of the neprilysin 2 active site based on the X-ray structure of neprilysin. Identification of residues involved in substrate hydrolysis and inhibitor binding of neprilysin 2.
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J Biol Chem,
279,
46172-46181.
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C.Oefner,
A.D'Arcy,
A.Mac Sweeney,
S.Pierau,
R.Gardiner,
and
G.E.Dale
(2003).
High-resolution structure of human apo dipeptidyl peptidase IV/CD26 and its complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl]amino)-acetyl]-2-cyano-(S)-pyrrolidine.
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Acta Crystallogr D Biol Crystallogr,
59,
1206-1212.
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PDB code:
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C.Rougeot,
M.Messaoudi,
V.Hermitte,
A.G.Rigault,
T.Blisnick,
C.Dugave,
D.Desor,
and
F.Rougeon
(2003).
Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity.
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Proc Natl Acad Sci U S A,
100,
8549-8554.
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M.Selkti,
A.Tomas,
J.F.Gaucher,
T.Prangé,
M.C.Fournié-Zaluski,
H.Chen,
and
B.P.Roques
(2003).
Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
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Acta Crystallogr D Biol Crystallogr,
59,
1200-1205.
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PDB codes:
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N.M.Hooper,
and
A.J.Turner
(2003).
An ACE structure.
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Nat Struct Biol,
10,
155-157.
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S.Liu,
R.Guo,
L.G.Simpson,
Z.S.Xiao,
C.E.Burnham,
and
L.D.Quarles
(2003).
Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX.
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J Biol Chem,
278,
37419-37426.
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S.Tsubuki,
Y.Takaki,
and
T.C.Saido
(2003).
Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation.
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Lancet,
361,
1957-1958.
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J.A.Carson,
and
A.J.Turner
(2002).
Beta-amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases?
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J Neurochem,
81,
1-8.
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L.Bianchetti,
C.Oudet,
and
O.Poch
(2002).
M13 endopeptidases: New conserved motifs correlated with structure, and simultaneous phylogenetic occurrence of PHEX and the bony fish.
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Proteins,
47,
481-488.
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R.Rozenfeld,
X.Iturrioz,
B.Maigret,
and
C.Llorens-Cortes
(2002).
Contribution of molecular modeling and site-directed mutagenesis to the identification of two structural residues, Arg-220 and Asp-227, in aminopeptidase A.
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J Biol Chem,
277,
29242-29252.
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A.J.Turner,
R.E.Isaac,
and
D.Coates
(2001).
The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.
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Bioessays,
23,
261-269.
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B.P.Roques
(2001).
Insights into peptide and protein function: a convergent approach.
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J Pept Sci,
7,
63-73.
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C.K.Brown,
K.Madauss,
W.Lian,
M.R.Beck,
W.D.Tolbert,
and
D.W.Rodgers
(2001).
Structure of neurolysin reveals a deep channel that limits substrate access.
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Proc Natl Acad Sci U S A,
98,
3127-3132.
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PDB code:
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I.Kishimoto,
F.K.Hamra,
and
D.L.Garbers
(2001).
Apparent B-type natriuretic peptide selectivity in the kidney due to differential processing.
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Can J Physiol Pharmacol,
79,
715-722.
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N.Bonvouloir,
N.Lemieux,
P.Crine,
G.Boileau,
and
L.DesGroseillers
(2001).
Molecular cloning, tissue distribution, and chromosomal localization of MMEL2, a gene coding for a novel human member of the neutral endopeptidase-24.11 family.
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DNA Cell Biol,
20,
493-498.
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Y.Sekine-Aizawa,
E.Hama,
K.Watanabe,
S.Tsubuki,
M.Kanai-Azuma,
Y.Kanai,
H.Arai,
H.Aizawa,
N.Iwata,
and
T.C.Saido
(2001).
Matrix metalloproteinase (MMP) system in brain: identification and characterization of brain-specific MMP highly expressed in cerebellum.
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Eur J Neurosci,
13,
935-948.
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W.Lian,
G.Chen,
D.Wu,
C.K.Brown,
K.Madauss,
L.B.Hersh,
and
D.W.Rodgers
(2000).
Crystallization and preliminary analysis of neurolysin.
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Acta Crystallogr D Biol Crystallogr,
56,
1644-1646.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
