Stabilization of the E* Form Turns Thrombin into an Anticoagulant*

AUTOR(ES)

Bah, Alaji

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

Previous studies have shown that deletion of nine residues in the autolysis loop of thrombin produces a mutant with an anticoagulant propensity of potential clinical relevance, but the molecular origin of the effect has remained unresolved. The x-ray crystal structure of this mutant solved in the free form at 1.55 Å resolution reveals an inactive conformation that is practically identical (root mean square deviation of 0.154 Å) to the recently identified E* form. The side chain of Trp215 collapses into the active site by shifting >10 Å from its position in the active E form, and the oxyanion hole is disrupted by a flip of the Glu192–Gly193 peptide bond. This finding confirms the existence of the inactive form E* in essentially the same incarnation as first identified in the structure of the thrombin mutant D102N. In addition, it demonstrates that the anticoagulant profile often caused by a mutation of the thrombin scaffold finds its likely molecular origin in the stabilization of the inactive E* form that is selectively shifted to the active E form upon thrombomodulin and protein C binding.

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