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PDBsum entry 2iux
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Human tace mutant g1234
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Structure:
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Angiotensin-converting enzyme. Chain: a. Fragment: residues 68-658. Synonym: human tace g1234 mutant, testis-specific isoform, ace-t, dipeptidyl carboxypeptidase i, kininase ii. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: chinese hamster ovary cells
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Resolution:
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2.80Å
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R-factor:
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0.201
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R-free:
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0.237
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Authors:
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J.M.Watermeyer,B.T.Swell,R.Natesh,H.R.Corradi,K.R.Acharya, E.D.Sturrock
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Key ref:
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J.M.Watermeyer
et al.
(2006).
Structure of testis ACE glycosylation mutants and evidence for conserved domain movement.
Biochemistry,
45,
12654-12663.
PubMed id:
DOI:
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Date:
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07-Jun-06
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Release date:
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25-Oct-06
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PROCHECK
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Headers
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References
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P12821
(ACE_HUMAN) -
Angiotensin-converting enzyme from Homo sapiens
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Seq:
Struc:
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1306 a.a.
577 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.15.1
- peptidyl-dipeptidase A.
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Reaction:
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Release of a C-terminal dipeptide, oligopeptide-|-Xaa-Xbb, when Xaa is not Pro, and Xbb is neither Asp nor Glu. Converts angiotensin I to angiotensin II.
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Cofactor:
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Zn(2+)
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DOI no:
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Biochemistry
45:12654-12663
(2006)
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PubMed id:
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Structure of testis ACE glycosylation mutants and evidence for conserved domain movement.
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J.M.Watermeyer,
B.T.Sewell,
S.L.Schwager,
R.Natesh,
H.R.Corradi,
K.R.Acharya,
E.D.Sturrock.
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ABSTRACT
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Human angiotensin-converting enzyme is an important drug target for which little
structural information has been available until recent years. The slow progress
in obtaining a crystal structure was due to the problem of surface
glycosylation, a difficulty that has thus far been overcome by the use of a
glucosidase-1 inhibitor in the tissue culture medium. However, the prohibitive
cost of these inhibitors and incomplete glucosidase inhibition makes alternative
routes to minimizing the N-glycan heterogeneity desirable. Here, glycosylation
in the testis isoform (tACE) has been reduced by Asn-Gln point mutations at
N-glycosylation sites, and the crystal structures of mutants having two and four
intact sites have been solved to 2.0 A and 2.8 A, respectively. Both mutants
show close structural identity with the wild-type. A hinge mechanism is proposed
for substrate entry into the active cleft, based on homology to human ACE2 at
the levels of sequence and flexibility. This is supported by normal-mode
analysis that reveals intrinsic flexibility about the active site of tACE.
Subdomain II, containing bound chloride and zinc ions, is found to have greater
stability than subdomain I in the structures of three ACE homologues.
Crystallizable glycosylation mutants open up new possibilities for
cocrystallization studies to aid the design of novel ACE inhibitors.
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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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C.S.Anthony,
H.R.Corradi,
S.L.Schwager,
P.Redelinghuys,
D.Georgiadis,
V.Dive,
K.R.Acharya,
and
E.D.Sturrock
(2010).
The N domain of human angiotensin-I-converting enzyme: the role of N-glycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407.
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J Biol Chem,
285,
35685-35693.
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PDB codes:
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E.G.Erdös,
F.Tan,
and
R.A.Skidgel
(2010).
Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function.
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Hypertension,
55,
214-220.
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G.A.Dalkas,
D.Marchand,
J.C.Galleyrand,
J.Martinez,
G.A.Spyroulias,
P.Cordopatis,
and
F.Cavelier
(2010).
Study of a lipophilic captopril analogue binding to angiotensin I converting enzyme.
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J Pept Sci,
16,
91-97.
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J.M.Watermeyer,
W.L.Kröger,
H.G.O'Neill,
B.T.Sewell,
and
E.D.Sturrock
(2010).
Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.
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Biochem J,
428,
67-74.
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PDB code:
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S.M.Danilov,
S.Kalinin,
Z.Chen,
E.I.Vinokour,
A.B.Nesterovitch,
D.E.Schwartz,
O.Gribouval,
M.C.Gubler,
and
R.D.Minshall
(2010).
Angiotensin I-converting enzyme Gln1069Arg mutation impairs trafficking to the cell surface resulting in selective denaturation of the C-domain.
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PLoS One,
5,
e10438.
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H.G.O'Neill,
P.Redelinghuys,
S.L.Schwager,
and
E.D.Sturrock
(2008).
The role of glycosylation and domain interactions in the thermal stability of human angiotensin-converting enzyme.
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Biol Chem,
389,
1153-1161.
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I.V.Balyasnikova,
R.Metzger,
F.E.Franke,
N.Conrad,
H.Towbin,
D.E.Schwartz,
E.D.Sturrock,
and
S.M.Danilov
(2008).
Epitope mapping of mAbs to denatured human testicular ACE (CD143).
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Tissue Antigens,
72,
354-368.
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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
