 |
PDBsum entry 1c4u
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hydrolase/hydrolase inhibitor
|
PDB id
|
|
|
|
1c4u
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structure of thrombin complexed with selective non-Electrophilic inhibitors having cyclohexyl moieties at p1.
|
|
|
Authors
|
|
R.Krishnan,
I.Mochalkin,
R.Arni,
A.Tulinsky.
|
|
|
Ref.
|
|
Acta Crystallogr D Biol Crystallogr, 2000,
56,
294-303.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The crystal structures of five new non-electrophilic beta-strand-templated
thrombin active-site inhibitors have been determined bound to the enzyme. Four
co-crystallize with hirugen and inhibitor isomorphously to produce
thrombin-hirugen crystals (monoclinic, space group C2), while one
co-crystallizes in the hexagonal system, space group P6(5). A 1,4-substituted
cyclohexyl moiety is conserved at the P1 position of all the inhibitors, along
with a fused hetero-bicyclic five- and six-membered ring that occupies the P2
site. Amino, amidino and aminoimidazole groups are attached to the cyclohexyl
ring for recognition at the S1 specificity site, while benzylsulfonyl and
diphenyl groups enhance the binding at the S3 subsite. The cyclohexyl groups at
the P1 positions of three of the inhibitors appear to be in the energetically
favored chair conformation, while the imidazole-substituted cyclohexyl rings are
in a boat conformation. Somewhat unexpectedly, the two cyclohexyl-aminoimidazole
groups bind differently in the specificity site; the unique binding of one is
heretofore unreported. The other inhibitors generally mimic arginyl binding at
S1. This group of inhibitors combines the non-electrophilicity and selectivity
of DAPA-like compounds and the more optimal binding features of the S1-S3 sites
of thrombin for peptidic molecules, which results in highly potent (binding
constants 12 nM-16 pM, one being 1.1 microM) and selective (ranging from 140 to
20 000 times more selective compared with trypsin) inhibitors of thrombin. The
binding modes of these novel inhibitors are correlated with their binding
constants, as is their selectivity, in order to provide further insight for the
design of therapeutic antithrombotic agents that inhibit thrombin directly at
the active site.
|
|
|
|
|
|
|
|
Figure 4.
Figure 4 Stereoview of superposed MOL356 and MOL592 bound to
thrombin. MOL356 (red), MOL592 (blue); thrombin of MOL356
complex numbered in atom colors; broken lines, principal
hydrogen bonds.
|
|
Figure 5.
Figure 5 Schematic of hydrogen-bonded salt bridges of
Molecumetics inhibitors with Asp189 of the S1 specificity site
of thrombin. MOL354 and MOL1245 shown together in one schematic;
values for MOL1245 are in parentheses.
|
|
|
|
|
|
The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2000,
56,
294-303)
copyright 2000.
|
|
|
|
|
|
|
