His57

His57 refers to a histidine residue at position 57 in the chymotrypsin numbering scheme used for serine proteases. This residue is highly conserved and is a key component of the catalytic triad Ser195–His57–Asp102 found in chymotrypsin-like enzymes, where His57 plays a central role inactivate or catalyze proteolysis.

Functionally, His57 acts as a general base during catalysis. It accepts a proton from Ser195, enabling Ser195 to attack the substrate’s carbonyl carbon and form a tetrahedral intermediate. The nearby Asp102 helps position and modulate the properties of His57 by stabilizing its imidazole ring, thereby tuning its pKa to facilitate proton transfer. In the catalytic cycle, His57 also participates in proton shuttling to facilitate the breakdown of intermediates and release of the peptide fragment, contributing to both acylation and deacylation steps.

Structurally, His57 resides in the active site in close proximity to Ser195 and Asp102. Its imidazole ring forms hydrogen bonds with catalytic partners and surrounding residues, creating an electrostatic and hydrogen-bond network that supports efficient proton transfers. The residue is nearly universally conserved among serine proteases of the chymotrypsin family, reflecting its essential role in catalytic competence and enzymatic efficiency.

Mutagenesis studies show that replacing His57 with nonfunctional residues typically abolishes or severely diminishes protease activity, highlighting its critical function. The designation “57” reflects the chymotrypsin numbering scheme; in other proteins, the corresponding residue may occupy a different absolute position, even though it serves the same catalytic role.