Endothiapepsin-inhibitor complexes

The active-site cleft has a less open arrangement in renins than in the other aspartic proteinases. Many loops as well as the helix hc (residues 224-236) belonging to the C-domain (residues 190-302) are significantly closer to the active site in the renin structures compared to those of endothiapepsin-inhibitor complexes. This is partly due to a difference in relative position of the rigid body comprising the C-domain. For instance, there is a domain rotation of 4° and translation of 0.1 A in the human renin complex with respect to the endothiapepsin-difluorostatone complex. 

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. 

Endothiapepsin is a single-chain proteinase of 330 amino acids. The structure is largely of / -sheet type and consists of two related lobes of approximately 170 amino acids each. The active site resides in a pronounced cleft between the lobes. Inhibitors have been shown, by X-ray crystallography, to bind in the active site cleft in extended conformations. A detailed comparison of the X-ray structures of 21 inhibitor complexes is given by Bailey and Cooper [50]. The hydrogen bonds that position the inhibitor main chain in the active site cleft are largely conserved from one... 

Incorporation of glycol or vicinal diol analogs of the peptide bond (-CH(OH)-CH(OH)-) has led to potent inhibitors and the x-ray structure for one such compound complexed with endothiapepsin is available [27]. The first hydroxyl in... 

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