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

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*This structure record is obsolete.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)
Alpha Thrombin Light Chain
Molecule annotation
Alpha Thrombin Heavy Chain
Molecule annotation
Molecule annotation
Chemicals (7 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB