Comparisons of the Sequences, 3-D Structures and Mechanisms of Pepsin-Like and Retroviral Aspartic Proteinases
The discovery of pseudo-two fold symmetry in the 3-D structures of the pepsin-like aspartic proteinases by Tang, James, Blundell and coworkers (Tang et al., 1978) has led to a productive series of hypotheses in subsequent years. These hypotheses concerned a dimeric ancestor of the aspartic proteinases (Tang et al., 1978), the close equivalence of the two active site aspartates (Pearl & Blundell, 1984), the similarity of the specificity sites on either side of the scissile bond (Blundell et al., 1983) and the structure of the retroviral proteinases as dimeric homologues of the pepsins (Pearl & Taylor, 1987; Blundell et al., 1988). Now that the crystal structures of several pepsins, retroviral proteinases and their inhibitors have been defined by X-ray analysis (see other chapters in this volume), these ideas can be reassessed more precisely and usefully. In this paper we provide short descriptions of the relationships between the secondary and tertiary structures of the two lobes of aspartic proteinases and the subunits of retroviral proteinases. We use these to provide an optimal alignment of sequences, an identification of residues that are important to the “aspartic proteinase fold” and a phylogenetic tree of structures. We describe the analogies between inhibitor binding of the retroviral and cellular proteinases and the rigid group rotations that are consequential upon occupation of the specificity pockets. Finally we discuss a mechanism of hydrolysis that is consistent with the structures of this family of enzymes.
KeywordsActive Site Residue Aspartic Proteinase Hydroxyl Oxygen Active Site Cleft Specificity Pocket
Unable to display preview. Download preview PDF.
- Blow, D. M., 1976 Acc. Chem. Res. 9: 145–152.Google Scholar
- Blundell, T. L., Jenkins, J. A., Pearl, L. H. & Sewell, T. S., 1985, in: “Aspartic Proteinases and Their Inhibitors,” Kostka, V., ed., pp.151–161, Walter de Gruyter, Berlin.Google Scholar
- Fitzgerald, P. M. D., McKeever, B. M., Van Middlesworth, J. F., Springer, J. P., Heimbach, J. C., Leu, C.-T., Herber, W. K., Dixon, R. A. F. & Darke, P. L., 1990, J. Mol. Biol 265: 14205–14219.Google Scholar
- Foundling, S. I., Cooper, S. I., Watson, J., Cleasby, F. E., Pearl, L. H., Sibanda, B. L., Hemmings, A., Wood, S. P., Blundell, T. L., Valler, M. J., Kay, J., Boger, J., Dunn, B. M., Leckie, B. J., Jones, D. M., Atrash, B., Hallett, A. & Szelke, M., 1987, Nature 327: 349–352.PubMedCrossRefGoogle Scholar
- Hoover, D., Veerapandian, B., Cooper, J. B., Rosati, R., Dominy, B. W., Damon, D. & Blundell, T. L., 1991, this volume.Google Scholar
- Šali, A., Cooper, J. B., Hofmann, T., Veerapandian, B. & Blundell, T. L., 1991, The Proteins in press.Google Scholar
- Tang, J., 1990, unpublished results.Google Scholar
- Veerapandian, B., Cooper, J. B., Šali, A., Blundell, T. L., Rosatti, R. L., Dominy, B. W., Damon, D. B., & Hoover, D., 1992, Protein Science, in press.Google Scholar
- Wilderspin, A., Hemmings, H. & Whittle, P. J., 1990, unpublished results.Google Scholar
- Zhu, Z-Y., Šali, A. & Blundell, T. L., 1991, unpublished results.Google Scholar