 |
PDBsum entry 1hbt
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
1hbt
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin.
|
|
|
Authors
|
|
P.H.Rehse,
T.Steinmetzer,
Y.Li,
Y.Konishi,
M.Cygler.
|
|
|
Ref.
|
|
Biochemistry, 1995,
34,
11537-11544.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
|
|
|
|
Abstract
|
|
|
The crystal structure of a complex between a bivalent peptidyl pyridinium methyl
ketone inhibitor and human alpha-thrombin has been solved and refined at 2.0 A
to an R factor of 0.18. The inhibitor,
(D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp-
Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which
forms a reversible covalent complex with thrombin, is highly potent with a Ki =
4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant hirudin. The N-terminal,
active-site-directed portion of the inhibitor is linked to the fibrinogen
recognition exosite binding portion by a tetraglycine segment. The strong
electron-withdrawing effect provided by the permanent positive charge on the
pyridinium nitrogen makes the arginyl carbonyl carbon more susceptible to
nucleophilic attack. In the crystal, a covalent P596-thrombin complex is
observed. The electron density surrounding the active site portion and the
pyridinium of the inhibitor is very well defined, clearly showing the existence
of a covalent bond between the Ser195 O gamma and the now tetrahedral carbon of
the inhibitor. The decreased binding ability of thrombin inhibitors containing
N-terminal acetylation is discussed as is the effect of replacing the P3
(D)phenylalanine with (D)cyclohexylalanine. The electron density surrounding the
remainder of the inhibitor is generally well defined, the exceptions being the
C-terminal (D)Glu, the highly flexible tetraglycine linker, and some of the
solvent-directed side chains.(ABSTRACT TRUNCATED AT 250 WORDS)
|
|
|
|
|
|
|
