Engineering an anion-binding cavity in antichymotrypsin modulates the "spring-loaded" serpin-protease interaction.

Article Details

Citation

Lukacs CM, Rubin H, Christianson DW

Engineering an anion-binding cavity in antichymotrypsin modulates the "spring-loaded" serpin-protease interaction.

Biochemistry. 1998 Mar 10;37(10):3297-304.

PubMed ID
9521649 [ View in PubMed
]
Abstract

Expressed in a kinetically trapped folding state, a serpin couples the thermodynamic driving force of a massive beta-sheet rearrangement to the inhibition of a target protease. Hence, the serpin-protease interaction is the premier example of a "spring-loaded" protein-protein interaction. Amino acid substitutions in the hinge region of a serpin reactive loop can weaken the molecular spring, which converts the serpin from an inhibitor into a substrate. To probe the molecular basis of this conversion, we report the crystal structure of A349R antichymotrypsin in the reactive loop cleaved state at 2.1 A resolution. This amino acid substitution does not block the beta-sheet rearrangement despite the burial of R349 in the hydrophobic core of the cleaved serpin along with a salt-linked acetate ion. The inhibitory activity of this serpin variant is not obliterated; remarkably, its inhibitory properties are anion-dependent due to the creation of an anion-binding cavity in the cleaved serpin.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Alpha-1-antichymotrypsinP01011Details