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Identification of the site of binding of sulfated, low molecular weight lignins on thrombin. Biochem Biophys Res Commun 2011 Sep 23;413(2):348-52



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Pubmed Central ID




Scopus ID

2-s2.0-80053109628 (requires institutional sign-in at Scopus site)   22 Citations


Sulfated, low molecular weight lignins (LMWLs), designed recently as macromolecular mimetics of the low molecular weight heparins (LMWHs), were found to exhibit a novel allosteric mechanism of inhibition of human thrombin, factor Xa and plasmin, which translates into potent human blood anticoagulation potential. To identify the site of binding of sulfated LMWLs, a panel of site-directed thrombin mutants was studied. Substitution of alanine for Arg(93) or Arg(175) induced a 7-8-fold decrease in inhibition potency, while Arg(165)Ala, Lys(169)Ala, Arg(173)Ala and Arg(233)Ala thrombin mutants displayed a 2-4-fold decrease. Other exosite 2 residues including those that play an important role in heparin binding, such as Arg(101), Lys(235), Lys(236) and Lys(240), did not induce any deficiency in sulfated LMWL activity. Thrombin mutants with multiple alanine substitution of basic residues showed a progressively greater defect in inhibition potency. Comparison of thrombin, factor Xa, factor IXa and factor VIIa primary sequences reiterated Arg(93) and Arg(175) as residues likely to be targeted by sulfated LMWLs. The identification of a novel site on thrombin with capability of allosteric modulation is expected to greatly assist the design of new regulators based on the sulfated LMWL scaffold.

Author List

Abdel Aziz MH, Mosier PD, Desai UR


Philip Mosier PhD Assistant Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Substitution
Binding Sites
Crystallography, X-Ray
Heparin, Low-Molecular-Weight
Molecular Weight
Mutagenesis, Site-Directed