Cooperative Interactions of Three Hotspot Heparin Binding Residues Are Critical for Allosteric Activation of Antithrombin by Heparin.

ABSTRACT: Heparin allosterically activates the anticoagulant serpin, antithrombin, by binding through a sequence-specific pentasaccharide and inducing activating conformational changes in the protein. Three basic residues of antithrombin, Lys114, Lys125, and Arg129, have been shown to be hotspots for binding the pentasaccharide, but the molecular basis for such hotspot binding has been unclear. To determine whether this results from cooperative interactions, we analyzed the effects of single, double, and triple mutations of the hotspot residues on pentasaccharide binding and activation of antithrombin. Double-mutant cycles revealed that the contribution of each residue to pentasaccharide binding energy was progressively reduced when one or both of the other residues were mutated, indicating strong c

SUBMITTER: Richard B 

PROVIDER: S-EPMC6363533 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature