Allostery in trypsin-like proteases suggests new therapeutic strategies

Trends Biotechnol. 2011 Nov;29(11):577-85. doi: 10.1016/j.tibtech.2011.06.001. Epub 2011 Jul 2.

Abstract

Trypsin-like proteases (TLPs) are a large family of enzymes responsible for digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis and immunity. A current paradigm posits that the irreversible transition from an inactive zymogen to the active protease form enables productive interaction with substrate and catalysis. Analysis of the entire structural database reveals two distinct conformations of the active site: one fully accessible to substrate (E) and the other occluded by the collapse of a specific segment (E*). The allosteric E*-E equilibrium provides a reversible mechanism for activity and regulation in addition to the irreversible zymogen to protease conversion and points to new therapeutic strategies aimed at inhibiting or activating the enzyme. In this review, we discuss relevant examples, with emphasis on the rational engineering of anticoagulant thrombin mutants.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Allosteric Regulation
  • Catalytic Domain
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Protein Engineering
  • Serine Endopeptidases / chemistry*
  • Serine Endopeptidases / metabolism*
  • Thrombin / chemistry
  • Thrombin / metabolism

Substances

  • Serine Endopeptidases
  • Thrombin