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Bell J.E.,Institute for Structural Biology and Drug Discovery | Bell J.K.,Center for the Study of Biological Complexity | Bell J.K.,Virginia Commonwealth University | Bell J.K.,University of Richmond
Journal of Biological Chemistry

Background: Suppressor of IkB kinase (SIKE) inhibits a key innate immune effector molecule, TANK-binding kinase 1 (TBK1), through an undefined mechanism. Results: SIKE is a TBK1 substrate. Conclusion: SIKE controls TBK1 activity by acting as a high affinity substrate. Significance: SIKE attenuates phosphorylation of interferon regulatory factor 3 (IRF3) by serving as an alternative, high affinity substrate for TBK1. © 2013 by The American Society. Source

Abdel Aziz M.H.,Virginia Commonwealth University | Abdel Aziz M.H.,Institute for Structural Biology and Drug Discovery | Sidhu P.S.,Virginia Commonwealth University | Sidhu P.S.,Institute for Structural Biology and Drug Discovery | And 10 more authors.
Journal of Medicinal Chemistry

Earlier, we reported on the design of sulfated benzofuran dimers (SBDs) as allosteric inhibitors of thrombin (Sidhu et al. J. Med. Chem.201154 5522-5531). To identify the site of binding of SBDs, we studied thrombin inhibition in the presence of exosite 1 and 2 ligands. Whereas hirudin peptide and heparin octasaccharide did not affect the IC 50 of thrombin inhibition by a high affinity SBD, the presence of full-length heparin reduced inhibition potency by 4-fold. The presence of γ′ fibrinogen peptide, which recognizes Arg93, Arg97, Arg173, Arg175, and other residues, resulted in a loss of affinity that correlated with the ideal Dixon-Webb competitive profile. Replacement of several arginines and lysines of exosite 2 with alanine did not affect thrombin inhibition potency, except for Arg173, which displayed a 22-fold reduction in IC 50. Docking studies suggested a hydrophobic patch around Arg173 as a plausible site of SBD binding to thrombin. The absence of the Arg173-like residue in factor Xa supported the observed selectivity of inhibition by SBDs. Cellular toxicity studies indicated that SBDs are essentially nontoxic to cells at concentrations as high as 250 mg/kg. Overall, the work presents the localization of the SBD binding site, which could lead to allosteric modulators of thrombin that are completely different from all clinically used anticoagulants. © 2012 American Chemical Society. Source

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