The structural puzzle of how serpin serine proteinase inhibitors work.

Abstract

Serine proteinase cleavage of proteins is essential to a wide variety of biological processes and is primarily regulated by protein inhibitors. Many inhibitors are conformationally rigid simulations of optimal serine proteinase substrates, which makes them highly efficient competitive inhibitors of target proteinases. In contrast, members of the serpin family of serine proteinase inhibitors display extensive flexibility and polymorphism, particularly in their reactive site segments and in beta-sheet secondary structure, which can take up and expel strands. Reactive site and beta-sheet polymorphism appear to be coupled in the serpins and may account for the extreme stability of serpin-proteinase complexes through the insertion of the reactive site strand into a beta-sheet. These unusual properties may have opened an adaptive pathway of proteinase regulation that was unavailable to the conformationally rigid proteinase inhibitors.