4N3L: Crystal Structure Of Thrombin In Complex With A Novel Glucose- Conjugated Potent Inhibitor

Citation:
Abstract
The beta-d-glucose-containing compound 3, bearing 2-chlorothiophene and 1-isopropylpiperidine moieties as binders of the S1 and S4 pockets, respectively, proved to be potent competitive inhibitor of factor Xa (fXa, Ki = 0.090 nM) and thrombin (fIIa, Ki = 100 nM). The potency of 3 increases, over the parent compound 1, against fIIa (110-fold), much more than against fXa (7-fold). Experimental deconstruction of 3 into smaller fragments revealed a binding cooperativity of the P3/P4 and propylene-linked beta-d-glucose fragments, stronger in fIIa (15.5 kJ.mol(-1)) than in fXa (2.8 kJ.mol(-1)). The crystal structure of human fIIa in complex with 3 revealed a binding mode including a strong H-bond network between the glucose O1', O3', and O5' and two critical residues, namely R221a and K224, belonging to the Na(+)-binding site which may allosterically perturb the specificity sites. The potential of 3 as antithrombotic agent was supported by its ability to inhibit thrombin generation and to stimulate fibrinolysis at submicromolar concentration.
PDB ID: 4N3LDownload
MMDB ID: 114795
PDB Deposition Date: 2013/10/7
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 1.94  Å
Source Organism:
Homo sapiens

*This structure record is obsolete.

Molecular Components in 4N3L
Label Count Molecule
Proteins (3 molecules)
1
Alpha Thrombin Light Chain
Molecule annotation
1
Alpha Thrombin Heavy Chain
Molecule annotation
1
Hirugen
Molecule annotation
Chemicals (7 molecules)
1
6
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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