Renin Crystal Structure

Tong L, Pav S, Lamarre D, Pilote L, Laplante S, Anderson PC, Jung G. High resolution crystal-structures of recombinant human renin in complex with polyhydroxymonoamide inhibitors. J Mol Biol 1995 250 211-222. 

Further optimization of the P3 substituent revealed that 3,4-bis-alkoxy substitution of the phenyl ring improved potency, with the optimal combination 3-(3-methoxypropoxy) and 4-methoxy (7, Table 2). Compound 7 exhibits exceptional renin inhibitory activity in both buffer and plasma and showed moderate in vivo activity in telemetered, sodium-depleted marmosets, with peak reduction of mean arterial pressure of 9 mm Hg and an 8-h duration of action.20 An X-ray co-crystal structure of compound 7 with recombinant human renin established that the methoxypropoxy sidechain occupies a narrow nonsubstrate pocket, termed S3sp. The importance of terminal methoxy group is... 

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. 

Figure 4. Stereoview of the X-ray crystal structure of a renin inhibitor, Smo-Phe-Ets-ACDMH (yellow), bound in endothiapepsin [17]. The hydrogen bond between the PI hydroxyl and Gly76(NH) (magenta) is shown by a white dotted line. The catalytic aspartic acids are shown in red.

Figure 6. Stereoview of the bound conformation of a phenyl tethered analog (upper, black lines) and a naphthyl tethered analog (lower, black lines) overlaid with Smo-Phe-Ets-ACDMH (gray lines) extracted from the endothiapepsin X-ray crystal structure [17] and oriented in the renin model active site.

Figure 7. Stereoview of the human renin X-ray crystal structure bound with an inhibitor [43]. The inhibitor is shown in yellow and the enzyme in red with the catalytic aspartic acids, the polyproline loop and Prolll on helix his,2 colored cyan.

Figure 8. Stereoview of renin inhibitors extracted from the X-ray crystal structures of three different aspartic proteases. The yellow inhibitor, 20, is from an HIV-1 protease structure (unpublished), the cyan inhibitor is from an endothiapepsin structure [17] and the green inhibitor is from a renin structure [43],...

Rahuel, J., Priestle, J.P., Griitter, M.G. The crystal structures of recombinant glycosylated human renin alone and in complex with a transition-state analog inhibitor. J. Struct. Biol. 1991, 107, 227-236. 

The crystal structure of HIV-1 protease was solved in 1989 and was shown to be similar to those of a family of enzymes known as aspartic proteases, of which renin is a member. Aspartic proteases have an active site containing two aspartic acid residues. 

Frazao C, C Topham, V Dhanaraj and T L Blundell 1994. Comparative Modelling of Human Renin- A Retrospective Evaluation of the Model with Respect to the X-ray Crystal Structure. Pure and Applied Chemistry 66 43-50. 

Frazao, C., Topham, C., Dhanaraj, V. and Blundell, T.L. (1994) Comparative modelling of human renin a retrospective evaluation of the model with respect to the X-ray crystal structure. Pure Appl. Chem. 66 43-50. 

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