The 1.8 A structure of the complex between chymostatin and Streptomyces griseus protease A. A model for serine protease catalytic tetrahedral intermediates.
The naturally occurring serine protease inhibitor, chymostatin, forms a hemiacetal adduct with the catalytic Ser195 residue of Streptomyces griseus protease A. Restrained parameter least-squares refinement of this complex to 1.8 A resolution has produced an R index of 0 X 123 for the 11,755 observed reflections. The refined distance of the carbonyl carbon atom of the aldehyde to O gamma of Ser195 is 1 X 62 A. Both the R and S configurations of the hemiacetal occur in equal populations, with the end result resembling the expected configuration for a covalent tetrahedral product intermediate of a true substrate. This study strengthens the concept that serine proteases stabilize a covalent, tetrahedrally co-ordinated species and elaborates those features of the enzyme responsible for this effect. We propose that a major driving force for the hydrolysis of peptide bonds by serine proteases is the non-planar distortion of the scissile bond by the enzyme, which thereby lowers the activation energy barrier to hydrolysis by eliminating the resonance stabilization energy of the peptide bond.
D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D003201:Computers; D003461:Crystallography; D010450:Endopeptidases; D006639:Histidine; D008968:Molecular Conformation; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors; D012697:Serine Endopeptidases
D001426:Bacterial Proteins; D009842:Oligopeptides; D011480:Protease Inhibitors; D006639:Histidine; C002101:chymostatin; D010450:Endopeptidases; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C024983:streptogrisin A