Structure renin

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. 

The models of the renin structure indicated that the P2 subsite was narrow at the backbone region, so disubstitution of the P2 a-carbon was not recommended. Subsequent experimental evidence confirmed this prediction. In one particular series, where epimerization of the aminomalonate at the P2 site of inhibitor 4 (Table 1) was a concern [27], the a-methyl deriv-... 

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 The yellow inhibitor, 20, is from an HIV-1 protease structure (unpublished), the cyan inhibitor is from an endothiapepsin structure [17] and the green inhibitor is from a renin structure [43],...

Summary Comparison of HIV-1 Protease versus Renin Structure-Based Design... 

Hashimoto, N., et al. Renin inhibitor relationship between molecular structure and oral absorption. Pharm. Res. 1994, 11, 1443-1447. 

Carilli, J. A. Lewicki, J. D. Baxter, and M. N. James, Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution, Science 243 1346 (1989). 

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

Compound No. Structure IC50 (M), Human Plasma Renin... 

While the rate limiting step of the cascade is the renin release, the biological active component is the octapeptide angiotensin n. It is an essential regulator of fluid and electrolyte balance as well as blood pressure. It exerts its actions on various structures like blood vessels, adrenal cortex, kidney and central nervous system. Although at least two different receptor subtypes for angiotensin II have been identified (ATi and AT2) the ATi-subtype is responsible for most of the cardiovascular effects of the agonist. 

The three-dimensional structures of human (left) and mouse renins (right) showing oligopeptide inhibitors bound in the active site cleft. The cleft lies between the N- and C-terminal domains of the enzyme and is approximately perpendicular to the plane of the page. It can accommodate 9-10 residues with the substrate/inhibitor bound in an extended conformation. The catalytic aspartic acid residues (not shown) are centrally placed at the base of the cleft. 

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