Pepsin-inhibitor complex

In subsequent observations S7c), the authors noted that acidification of all 3 pepsinogens to pH 2 for 8 minutes, followed by incubation at various pH s, from 1.1 to 7.2, and then alkalinization at pH 7.8, leads to formation of intermediate compounds between pepsinogens and pepsins. These were designated as pepsin-pepsin-inhibitor complexes (HPPI). These complexes have no milk-clotting activity at pH 5.5 and... 

Pepsin is the protein-cleaving enzyme of the stomach. The precursor, pepsinogen, is formed by the gastric mucosa. It is a protein with a molecular weight of 42,600 which has been obtained in crystalline form. In an acidic medium, or by the action of pepsin itself, the zymogen is converted to the active enzyme. This conversion reaction is autocatalytic, because the catalyst, pepsin, appears as the reaction product. Nevertheless, it passes through an inactive intermediate step, a pepsin-inhibitor complex ... 

Free Energy Calculations on Enzyme-Inhibitor Complexes Studies of Thermolysin and Rhizopus Pepsin... 

The mutation of the hydroxyl group positioned in R-configuration at the C(3) atom of the central statine (rSta) residue of the inhibitor gives rise to AAGbind of -0.51 kcal/mol, which is very close to the experimental value of -0.8 kcal/mol. It may be noted here that the starting configuration of the inhibitor in the enzyme-inhibitor complex is the same as that of pepstatin. The crystal structure of rhizopus pepsin or any other aspartic proteinase... 

There is also great similarity between aspartic proteinases in terms of interactions with the transition-state analog inhibitors at the catalytic center. The catalytic aspartyl side chains and the inhibitor hydroxyl group are essentially superimposable in both renin complexes. The isostere C-OH bonds lie at identical positions when the structures of inhibitor complexes of several aspartic proteinases are superposed, in spite of the differences in the sequence and secondary structure. Most of the complex array of hydrogen bonds found in endothiapepsin complexes are formed in renin with the exception of that to the threonine or serine at 218, which is replaced by alanine in human renin. The similarity can be extended to all other pepsin-like aspartic proteinases and even to the retroviral proteinases [44,45]. This implies that the recognition of the transition state is conserved in evolution, and the mechanisms of this divergent group of proteinases must be very similar. 

K. Suguna, E. A. Padlan, R. Bott, J. Boger, K. D. Parris, and D. R. Davies, Structures of complexes of rhizopus pepsin with pepstatin and other statine-containing inhibitors, Proteins 13 195 (1992). 

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