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  • Title: High resolution crystal structures of free thrombin in the presence of K(+) reveal the molecular basis of monovalent cation selectivity and an inactive slow form.
    Author: Carrell CJ, Bush LA, Mathews FS, Di Cera E.
    Journal: Biophys Chem; 2006 Jun 01; 121(3):177-84. PubMed ID: 16487650.
    Abstract:
    Structural biology has recently advanced our understanding of the molecular mechanisms of activation and selectivity in monovalent cation activated enzymes. Here we report a 1.9 Angstrom resolution crystal structure of free thrombin, a Na(+) selective enzyme, in the presence of KCl. There are two molecules in the asymmetric unit, one with the cation site bound to K(+) and the other with this site free. The K(+)-bound form shows key differences compared with the Na(+)-bound structure that explain the different kinetics of activation. The cation-free form, on the other hand, assumes a conformation where the monovalent cation binding site is completely disordered, the S1 pocket is inaccessible to substrate and binding to exosite I is compromised by an unprecedented >20 Angstrom shift in the position of the autolysis loop. This form, named S(*), corresponds to the inactive Na(+)-free slow form identified by early kinetic studies. A simple model of thrombin allostery that incorporates the contribution of S(*) is proposed.
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