 |
PDBsum entry 1thr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase(serine proteinase)
|
PDB id
|
|
|
|
1thr
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor.
|
|
|
Authors
|
|
X.Qiu,
M.Yin,
K.P.Padmanabhan,
J.L.Krstenansky,
A.Tulinsky.
|
|
|
Ref.
|
|
J Biol Chem, 1993,
268,
20318-20326.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The structures of two hirudin-based fibrinogen recognition exosite peptide
inhibitors with significantly different sequences complexed with alpha-thrombin
at a site distinct from the active site (exosite) have been determined
crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic
peptide with some nonconventional amino acid residues (MDL-28050), and the other
is a natural COOH-terminal peptide isolated from the leech Hirudinaria
manillensis (hirullin P18). The structures have been refined by restrained least
squares methods to R values of 0.161 and 0.155, respectively. The first stretch
of each peptide, corresponding to hirudin 55-59, associates with thrombin
similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues
of the inhibitors interact with and bind to thrombin, the binding is
accomplished. through a rigid body conformational adjustment of the peptide with
respect to the conformation displayed by hirudin and hirugen (40 degrees
rotation about the Ile59, CA-C bond). This causes the side groups of
cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the
opposite direction of the all important Tyr63, ring of hirudin and hirugen but
permits the residues to penetrate and interact with the 3(10) turn hydrophobic
binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in
a different way by virtue of the substrate conformational readjustment. The
results show that the first stretch of peptide makes concerted and efficient
binding interactions with thrombin, and the peptide positions of the inhibitors
are fairly specific and homologous so that the stretch appears to be related to
specific recognition associated with the exosite. The relative flexibility of
structure and sequence of the second stretch is a display of tolerance of
imprecision by thrombin in its COOH-terminal hydrophobic association with
hirudin-based inhibitors.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Active site and exosite binding of alpha-Thrombin.
|
|
|
Authors
|
|
A.Tulinsky,
X.Qiu.
|
|
|
Ref.
|
|
Blood Coagul Fibrinolysis, 1993,
4,
305-312.
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
