Three-dimensional structure penicillopepsin

It is clear that a great deal of work is still required in the field of acid proteases before we reach the level of understanding attained for other groups of proteolytic enzymes. Fortunately the amino acid sequence work on at least three enzymes—pepsin, chymosin, and penicillopepsin— is well advanced, and complete three-dimensional structures should become available in the near future. A tentative structure for rhizopus-pepsin has been obtained, but in the absence of sufficient sequence information interpretation of the electron density maps is difficult. We can... 

Fig. 16.2. A section of the alignment of sequences of aspartic proteinases achieved by comparing the three-dimensional structures using COMPARER [14]. HIV human immunodeficiency virus RSV Rous sarcoma virus APE endothiapepsin APP penicillopepsin APR rhizopuspepsin PEP hexagonal porcine pepsin CHY calf chymosin. The last letter refers to the amino (N) or car-boxy (C) terminal domains of the pepsins. The coordinates of the three-dimensional structures were obtained from the PDB databank [24]. The amino acid code is the standard one-letter code (see Appendix C) formatted using the following conventions [7] ...

The method is applicable to any system where a three-dimensional structure of the receptor is available. The steps of the method are described below and illustrated using the enzyme penicillopepsin, an aspartyl protease. 

In view of the three-dimensional structure of penicillopepsin that we have observed, we are in a position to contribute to an understanding of the mechanism of acid protease catalysis. Any mechanism describing the catalytic event must, of course, be consistent with a number of known facts regarding these enzymes as deduced from chemical and enzymic studies of the cleavage of small synthetic peptide substrates. Knowles has summarized these facts (35) and has presented a possible mechanism for the action of acid proteases (30,35). More recently, Fruton (36) has reviewed the acid protease field and in the following discussion we have attempted to... 

A number of chemical approaches have been used in the design of renin inhibitors. In the absence of the purified enzyme, most of the early search for inhibitors was carried out using crude renin preparations. The amino acid sequences of mouse, rat and human renin were obtained later on using either the traditional isolation and sequencing techniques or cDNA methodology. Various three-dimensional models of renin were constructed in the early stages, based on the x ray structures of other similar aspartyl proteases, for example endothia-pepsin and penicillopepsin. Later on, the X ray crystal structure of recombinant human renin was reported. The inhibitor design process has been based on some of these models. 

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