title: Substantial non-electrostatic forces are needed to induce allosteric disruption of thrombin's active site through exosite 2.
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.
authors.affiliation: Institute for Structural Biology & Drug Discovery and Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, United States.
authors.forename: Akul Y
authors.initials: AY
authors.lastname: Mehta
authors.affiliation: Institute for Structural Biology & Drug Discovery and Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: urdesai@vcu.edu.
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000494:Allosteric Regulation; D000925:Anticoagulants / Q000737:chemistry*; D020134:Catalytic Domain; D006493:Heparin / Q000737:chemistry; D007700:Kinetics; D008031:Lignin / Q000031:analogs & derivatives / Q000737:chemistry*; D018716:Molecular Mimicry; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry; D011485:Protein Binding; D012965:Sodium Chloride / Q000737:chemistry; D055672:Static Electricity; D013431:Sulfates / Q000737:chemistry; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000925:Anticoagulants; D019038:Platelet Glycoprotein GPIb-IX Complex; D013431:Sulfates; D012965:Sodium Chloride; D006493:Heparin; D008031:Lignin; D013917:Thrombin
keywords: Allosteric inhibition; Anticoagulants; Coagulation; Glycosaminoglycan mimetics; Thrombin