 |
PDBsum entry 4thn
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
4thn
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
The crystal structure of alpha-Thrombin-Hirunorm IV complex reveals a novel specificity site recognition mode.
|
|
|
Authors
|
|
A.Lombardi,
G.De simone,
F.Nastri,
S.Galdiero,
R.Della morte,
N.Staiano,
C.Pedone,
M.Bolognesi,
V.Pavone.
|
|
|
Ref.
|
|
Protein Sci, 1999,
8,
91-95.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The X-ray crystal structure of the human alpha-thrombin-hirunorm IV complex has
been determined at 2.5 A resolution, and refined to an R-factor of 0.173. The
structure reveals an inhibitor binding mode distinctive of a true hirudin
mimetic, which justifies the high inhibitory potency and the selectivity of
hirunorm IV. This novel inhibitor, composed of 26 amino acids, interacts through
the N-terminal end with the alpha-thrombin active site in a nonsubstrate mode,
and binds specifically to the fibrinogen recognition exosite through the
C-terminal end. The backbone of the N-terminal tripeptide Chg1"-Arg2"-2Na13"
(Chg, cyclohexyl-glycine; 2Na1, beta-(2-naphthyl)-alanine) forms a parallel
beta-strand to the thrombin main-chain segment Ser214-Gly216. The Chg1" side
chain occupies the S2 site, Arg2" penetrates into the S1 specificity site, while
the 2Na13" side chain occupies the aryl binding site. The Arg2" side chain
enters the S1 specificity pocket from a position quite apart from the canonical
P1 site. This notwithstanding, the Arg2" side chain establishes the typical ion
pair with the carboxylate group of Asp189.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
The structure of a complex of recombinant hirudin and human alpha-Thrombin.
|
|
|
Authors
|
|
T.J.Rydel,
K.G.Ravichandran,
A.Tulinsky,
W.Bode,
R.Huber,
C.Roitsch,
J.W.Fenton.
|
|
|
Ref.
|
|
Science, 1990,
249,
277-280.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #2
|
|
|
Title
|
|
Hirunorms are true hirudin mimetics. The crystal structure of human alpha-Thrombin-Hirunorm V complex.
|
|
|
Authors
|
|
G.De simone,
A.Lombardi,
S.Galdiero,
F.Nastri,
R.Della morte,
N.Staiano,
C.Pedone,
M.Bolognesi,
V.Pavone.
|
|
|
Ref.
|
|
Protein Sci, 1998,
7,
243-253.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Figure 1.
ig. 1. Schematic representation of different interaction mechanisms be-
thrombin inhibitors and thrombin.
|
|
Figure 2.
Fig. 2. Stereo views of the electron density map, contoured t lu, for the hirunorm V N-terminal tetrapeptide Chg'''-Thr4'' when bound
to thrombin active site (A) and for the C-terminal hirunorm V undecapeptide AS~'~'`-D-GIU*''` when bound to thrombin FRE (B).
|
|
|
|
|
|
The above figures are
reproduced from the cited reference
which is an Open Access publication published by the Protein Society
|
|
|
Secondary reference #3
|
|
|
Title
|
|
Rational design of true hirudin mimetics: synthesis and characterization of multisite-Directed alpha-Thrombin inhibitors.
|
|
|
Authors
|
|
A.Lombardi,
F.Nastri,
R.Della morte,
A.Rossi,
A.De rosa,
N.Staiano,
C.Pedone,
V.Pavone.
|
|
|
Ref.
|
|
J Med Chem, 1996,
39,
2008-2017.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Secondary reference #4
|
|
|
Title
|
|
Refined structure of the hirudin-Thrombin complex.
|
|
|
Authors
|
|
T.J.Rydel,
A.Tulinsky,
W.Bode,
R.Huber.
|
|
|
Ref.
|
|
J Mol Biol, 1991,
221,
583-601.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
