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PDBsum entry 2dqm
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.11.2
- membrane alanyl aminopeptidase.
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Reaction:
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Release of an N-terminal amino acid, Xaa-|-Xbb- from a peptide, amide or arylamide. Xaa is preferably Ala, but may be most amino acids including Pro (slow action). When a terminal hydrophobic residue is followed by a prolyl residue, the two may be released as an intact Xaa-Pro dipeptide.
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Cofactor:
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Zn(2+)
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DOI no:
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J Biol Chem
281:33664-33676
(2006)
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PubMed id:
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Crystal structure of aminopeptidase N (proteobacteria alanyl aminopeptidase) from Escherichia coli and conformational change of methionine 260 involved in substrate recognition.
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K.Ito,
Y.Nakajima,
Y.Onohara,
M.Takeo,
K.Nakashima,
F.Matsubara,
T.Ito,
T.Yoshimoto.
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ABSTRACT
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Aminopeptidase N from Escherichia coli is a broad specificity zinc exopeptidase
belonging to aminopeptidase clan MA, family M1. The structures of the
ligand-free form and the enzyme-bestatin complex were determined at 1.5- and
1.6-A resolution, respectively. The enzyme is composed of four domains: an
N-terminal beta-domain (Met(1)-Asp(193)), a catalytic domain
(Phe(194)-Gly(444)), a middle beta-domain (Thr(445)-Trp(546)), and a C-terminal
alpha-domain (Ser(547)-Ala(870)). The structure of the catalytic domain exhibits
similarity to thermolysin, and a metal-binding motif (HEXXHX(18)E) is found in
the domain. The zinc ion is coordinated by His(297), His(301), Glu(320), and a
water molecule. The groove on the catalytic domain that contains the active site
is covered by the C-terminal alpha-domain, and a large cavity is formed inside
the protein. However, there exists a small hole at the center of the C-terminal
alpha-domain. The N terminus of bestatin is recognized by Glu(121) and Glu(264),
which are located in the N-terminal and catalytic domains, respectively.
Glu(298) and Tyr(381), located near the zinc ion, are considered to be involved
in peptide cleavage. A difference revealed between the ligand-free form and the
enzyme-bestatin complex indicated that Met(260) functions as a cushion to accept
substrates with different N-terminal residue sizes, resulting in the broad
substrate specificity of this enzyme.
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Selected figure(s)
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Figure 6.
FIGURE 6. Protein surface stereo diagrams of peptidase
family M1 enzymes. a, aminopeptidase N; b, human leukotriene
A[4] hydrolase (Protein Data Bank code 1HS6); c, T. acidophilum
tricorn-interacting factor F3 (Protein Data Bank code 1Z1W). The
three enzymes are indicated in the respective colors used to
represent corresponding regions based on the domains of
aminopeptidase N, i.e. N-terminal  -domain (blue),
catalytic domain (cyan), middle -domain (green), and
C-terminal  -domain (pink). The
arrows indicate the expected sites for the entry of substrates
into the active site of the three enzymes.
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Figure 8.
FIGURE 8. Catalytic mechanism of aminopeptidase N. a, free
enzyme; b, Michaelis complex; c, tetrahedral intermediate; d,
enzyme complexed with an amino acid product.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2006,
281,
33664-33676)
copyright 2006.
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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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J.Su,
Q.Wang,
J.Feng,
C.Zhang,
D.Zhu,
T.Wei,
W.Xu,
and
L.Gu
(2011).
Engineered Thermoplasma acidophilum factor F3 mimics human aminopeptidase N (APN) as a target for anticancer drug development.
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Bioorg Med Chem,
19,
2991-2996.
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PDB code:
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C.K.Chuang,
B.Rockel,
G.Seyit,
P.J.Walian,
A.M.Schönegge,
J.Peters,
P.H.Zwart,
W.Baumeister,
and
B.K.Jap
(2010).
Hybrid molecular structure of the giant protease tripeptidyl peptidase II.
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Nat Struct Mol Biol,
17,
990-996.
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PDB code:
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E.Menach,
K.Yasukawa,
and
K.Inouye
(2010).
Effects of site-directed mutagenesis of the loop residue of the N-terminal domain Gly117 of thermolysin on its catalytic activity.
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Biosci Biotechnol Biochem,
74,
2457-2462.
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S.Vaiyapuri,
S.C.Wagstaff,
K.A.Watson,
R.A.Harrison,
J.M.Gibbins,
and
E.G.Hutchinson
(2010).
Purification and functional characterisation of rhiminopeptidase A, a novel aminopeptidase from the venom of Bitis gabonica rhinoceros.
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PLoS Negl Trop Dis,
4,
e796.
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A.Singh,
and
C.Sivaprasad
(2009).
Functional interpretation of APN receptor from M.sexta using a molecular model.
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Bioinformation,
3,
321-325.
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C.Claperon,
I.Banegas-Font,
X.Iturrioz,
R.Rozenfeld,
B.Maigret,
and
C.Llorens-Cortes
(2009).
Identification of threonine 348 as a residue involved in aminopeptidase A substrate specificity.
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J Biol Chem,
284,
10618-10626.
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M.C.Fournié-Zaluski,
H.Poras,
B.P.Roques,
Y.Nakajima,
K.Ito,
and
T.Yoshimoto
(2009).
Structure of aminopeptidase N from Escherichia coli complexed with the transition-state analogue aminophosphinic inhibitor PL250.
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Acta Crystallogr D Biol Crystallogr,
65,
814-822.
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PDB code:
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M.Maruyama,
N.Arisaka,
Y.Goto,
Y.Ohsawa,
H.Inoue,
H.Fujiwara,
A.Hattori,
and
M.Tsujimoto
(2009).
Histidine 379 of human laeverin/aminopeptidase Q, a nonconserved residue within the exopeptidase motif, defines its distinctive enzymatic properties.
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J Biol Chem,
284,
34692-34702.
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Q.Li,
H.Fang,
X.Wang,
L.Hu,
and
W.Xu
(2009).
Novel cyclic-imide peptidomimetics as aminopeptidase N inhibitors. Design, chemistry and activity evaluation. Part I.
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Eur J Med Chem,
44,
4819-4825.
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S.McGowan,
C.J.Porter,
J.Lowther,
C.M.Stack,
S.J.Golding,
T.S.Skinner-Adams,
K.R.Trenholme,
F.Teuscher,
S.M.Donnelly,
J.Grembecka,
A.Mucha,
P.Kafarski,
R.Degori,
A.M.Buckle,
D.L.Gardiner,
J.C.Whisstock,
and
J.P.Dalton
(2009).
Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase.
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Proc Natl Acad Sci U S A,
106,
2537-2542.
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PDB codes:
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B.Salopek-Sondi,
B.Vukelić,
J.Spoljarić,
S.Simaga,
D.Vujaklija,
J.Makarević,
N.Jajcanin,
and
M.Abramić
(2008).
Functional tyrosine residue in the active center of human dipeptidyl peptidase III.
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Biol Chem,
389,
163-167.
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S.Ye,
S.Y.Chai,
R.A.Lew,
D.B.Ascher,
C.J.Morton,
M.W.Parker,
and
A.L.Albiston
(2008).
Identification of modulating residues defining the catalytic cleft of insulin-regulated aminopeptidase.
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Biochem Cell Biol,
86,
251-261.
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T.Zhou,
P.J.Enyeart,
and
C.O.Wilke
(2008).
Detecting clusters of mutations.
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PLoS ONE,
3,
e3765.
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Y.Nakajima,
K.Ito,
T.Toshima,
T.Egawa,
H.Zheng,
H.Oyama,
Y.F.Wu,
E.Takahashi,
K.Kyono,
and
T.Yoshimoto
(2008).
Dipeptidyl aminopeptidase IV from Stenotrophomonas maltophilia exhibits activity against a substrate containing a 4-hydroxyproline residue.
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J Bacteriol,
190,
7819-7829.
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PDB code:
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T.Yoshimoto
(2007).
[Biochemistry and structural biology of microbial enzymes and their medical applications]
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Yakugaku Zasshi,
127,
1035-1045.
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V.L.Pham,
M.S.Cadel,
C.Gouzy-Darmon,
C.Hanquez,
M.C.Beinfeld,
P.Nicolas,
C.Etchebest,
and
T.Foulon
(2007).
Aminopeptidase B, a glucagon-processing enzyme: site directed mutagenesis of the Zn2+-binding motif and molecular modelling.
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BMC Biochem,
8,
21.
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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
code is
shown on the right.
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Links
