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PDBsum entry 1qf0
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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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Crystal structures of alpha-Mercaptoacyldipeptides in the thermolysin active site: structural parameters for a zn monodentation or bidentation in metalloendopeptidases.
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Authors
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J.F.Gaucher,
M.Selkti,
G.Tiraboschi,
T.Prangé,
B.P.Roques,
A.Tomas,
M.C.Fournié-Zaluski.
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Ref.
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Biochemistry, 1999,
38,
12569-12576.
[DOI no: ]
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PubMed id
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Abstract
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Three alpha-mercaptoacyldipeptides differing essentially in the size of their
C-terminal residues have been crystallized in the thermolysin active site. A new
mode of binding was observed for 3 [HS-CH(CH(2)Ph)CO-Phe-Tyr] and 4
[HS-CH((CH(2))(4)CH(3))CO-Phe-Ala], in which the mercaptoacyl moieties act as
bidentates with Zn-S and Zn-O distances of 2.3 and 2.4 A, respectively, the side
chains fitting the S(1), S(1)', and S(2)' pockets. Moreover, a distance of 3.1 A
between the sulfur atom and the OE1 of Glu(143) suggests that they are H-bonded
and that one of these atoms is protonated. This H-bond network involving
Glu(143), the mercaptoacyl group of the inhibitor, and the Zn ion could be
considered a "modified" transition state mimic of the peptide bond hydrolysis.
Due to the presence of the hindering (5-phenyl)proline, the inhibitor
HS-CH(CH(2)Ph)CO-Gly-(5-Ph)Pro (2) interacts through the usual Zn monodentation
via the thiol group and occupancy of S(1)' and S(2)' subsites by the aromatic
moieties, the proline ring being outside the active site. The inhibitory
potencies are consistent with these structural data, with higher affinities for
3 (4.2 x 10(-)(8) M) and 4 (4.8 x 10(-)(8) M) than for 2 (1.2 x 10(-)(6) M). The
extension of the results, obtained with thermolysin being considered as the
model of physiological zinc metallopeptidases, allows inhibitor-recognition
modes for other peptidases, such as angiotensin converting enzyme and neutral
endopeptidase, to be proposed and opens interesting possibilities for the design
of new classes of inhibitors.
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Secondary reference #1
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Title
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Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-Converting enzyme with long duration of action.
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Authors
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M.C.Fournie-Zaluski,
P.Coric,
V.Thery,
W.Gonzalez,
H.Meudal,
S.Turcaud,
J.B.Michel,
B.P.Roques.
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Ref.
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J Med Chem, 1996,
39,
2594-2608.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Optimal recognition of neutral endopeptidase and angiotensin-Converting enzyme active sites by mercaptoacyldipeptides as a means to design potent dual inhibitors.
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Authors
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P.Coric,
S.Turcaud,
H.Meudal,
B.P.Roques,
M.C.Fournie-Zaluski.
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Ref.
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J Med Chem, 1996,
39,
1210-1219.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Structural analysis of zinc substitutions in the active site of thermolysin.
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Authors
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D.R.Holland,
A.C.Hausrath,
D.Juers,
B.W.Matthews.
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Ref.
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Protein Sci, 1995,
4,
1955-1965.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Three-Dimensional structure of thermolysin.
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Authors
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B.W.Matthews,
J.N.Jansonius,
P.M.Colman,
B.P.Schoenborn,
D.Dupourque.
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Ref.
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Nat New Biol, 1972,
238,
37-41.
[DOI no: ]
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PubMed id
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