Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin’s active site through exosite 2

Mehta AY, Desai UR. (2014) Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin’s active site through exosite 2. PMID: 25201728. PMCID: PMC4179500.

Abstract
Sulfated β-O4 lignin (SbO4L), a non-saccharide glycosaminoglycan mimetic, was recently disclosed as a novel exosite 2-directed thrombin inhibitor with the capability of mimicking sulfated tyrosine sequences of glycoprotein Ibα resulting in dual anticoagulant and antiplatelet activities. SbO4L engages essentially the same residues of exosite 2 as heparin and yet induces allosteric inhibition. Fluorescence spectroscopic studies indicate that SbO4L reduces access of the active site to molecular probes and affinity studies at varying salt concentrations show nearly 6 ionic interactions, similar to heparin, but much higher non-ionic contribution. The results suggest that subtle increase in non-electrostatic forces arising from SbO4L’s aromatic scaffold appear to be critical for inducing allosteric dysfunction of thrombin’s active site.

Copyright © 2014 Elsevier Inc. All rights reserved.

Link to journal: http://www.journals.elsevier.com/biochemical-and-biophysical-research-communications/

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KEYWORDS: Allosteric inhibition; Anticoagulants; Coagulation; Glycosaminoglycan mimetics; Thrombin