A proposed conformation of isoleucyl5-angiotensin II

Rr, Smeby; Arakawa, Kikuo; Bumpus, F. M.; Mm, Marsh

doi:10.1016/0006-3002(62)90065-3

Cited by 79 publications

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“…The data available concerning the secondary structure of angiotensin I1 are much less clear cut. Smeby et al [7] suggested that angiotensin I1 could adopt an a-helix configuration in aqueous solution, whereas Scheraga [8] was in favor of an unordered structure. The work of Paladini et al [9] and of Paiva [lo], on the other hand, suggested that several conformations are simultaneously present in aqueous solutions of angiotensin 11.…”

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“…As already suggested for some other short peptides, circular-dichroism spectra of angiotensinamide I1 show dramatic perturbations of the peptidic region due to side-chain aromatic-chromophore overlapping. The contribution of prolyl residue in position 7 of the peptide appears to be critical; equilibrium between cis and trans forms is believed to be shifted toward one or the other conformer upon binding to receptor site. This would result in the adequate positioning of the phenylalanine residue, the biological importance of which has already been shown.…”

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Studies of Angiotensin‐II Conformations by Circular Dichroism

Fermandjian¹,

Morgat²,

Fromageot³

1971

European Journal of Biochemistry

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Angiotensinamide I1 has been studied by circular-dichroism spectroscopy in comparison with some of its peptidic fragments and structural analogs. The following observations have been made. The stepwise examination of elongated peptides shows the appearance of a structural organisation at the heptapeptide stage. Evidence that C-terminal phenylalanine residue plays an important role on the overall conformation of the octapeptide is obtained. As already suggested for some other short peptides, circular-dichroism spectra of angiotensinamide I1 show dramatic perturbations of the peptidic region due to side-chain aromatic-chromophore overlapping. The contribution of prolyl residue in position 7 of the peptide appears to be critical; equilibrium between cis and trans forms is believed to be shifted toward one or the other conformer upon binding to receptor site. This would result in the adequate positioning of the phenylalanine residue, the biological importance of which has already been shown.Angiotensin I1 is a natural octapeptide [l] contributing to the regulation of several important physiological functions, among others the regulation of blood pressure [2], whence its name. To investigate the mode of action of angiotensin I1 a t the molecular level, three sets of information are required concerning: (a) the recognition of specific binding sites and their isolation, (b) the processes triggered when the binding sites are properly occupied and (c) the reciprocal adjustment of the hormone to the active sites responsible both for the extreme specificity of binding and for the triggering of the biological response.Recently rapid progress has been made concerning the characterization of specific binding sites [3] and of different classes of receptors [4], the calcium release in smooth muscles [5] and the formation of cyclic AMP [6]. The data available concerning the secondary structure of angiotensin I1 are much less clear cut. Smeby et al. [7] suggested that angiotensin I1 could adopt an a-helix configuration in aqueous solution, whereas Scheraga [8] was in favor of an unordered structure. The work of Paladini et al. [9] and of Paiva [lo], on the other hand, suggested that several conformations are simultaneously present in aqueous solutions of angiotensin 11. All these conclusions might reflect the fact that angiotensin I1 is a small peptide with linear primary structure. A predominant secondary structure may well require precise surrounding conditions. In the present paper we report an analysis by circular dichroism in the ultraviolet region between 300 nm and 185 nm of angiotensin-I1 solutions in various solvents and a t different temperatures.Comparison of the spectra of short peptides and of angiotensin I1 analogous with the spectra of the hormone itself, indicated that angiotensin I1 has a marked tendency to adopt a defined ordered conformation of ,&antiparallel structure. Triiluorethanol was from Fluka. Alkaline methanol was prepared by addition of 1 ml 2 N NaOH to 100 ml methanol. The range of concentrations of ...

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Studies of Angiotensin‐II Conformations by Circular Dichroism

Fermandjian¹,

Morgat²,

Fromageot³

1971

European Journal of Biochemistry

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“…It has been shown previously that the binding of All and related peptides to receptors requires well-defined conformational and dynamical properties of the tyrosine-4 and histidine-6 side chains (6)(7)(8)(9)(10)(11). It has also been shown that high agonist activity requires the presence of both the phenyl ring and the free carboxyl group at the COOH terminus (12) and that the juxtaposition of these groups is very important (13,14).…”

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Studies on angiotensin II and analogs: impact of substitution in position 8 on conformation and activity.

Aumelas¹,

Sakarellos²,

Lintner³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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Affinity, residual agonist activity, and inhibitor properties of a series of angiotensin II analogs modified at the COOH-terminal position (X8-substituted peptides) have been probed for structure/conformation-biological activity relationships. The results emphasize (t) the large impact that subtle conformational variations caused by structural alterations in the position 8 side chain have on biological properties, (it) the implication of the COOH-terminal carboxyl group in both affinity and intrinsic activity, and (Wi) the influence that the bulkiness of the side chain in position 8 of antagonists has on the local conformation at the COOH terminus and thus on the inhibitory properties. In the hormone, the phenylalanine-8 ring is required for its steric influence and aromaticity to ensure a fully active conformation at the COOH terminus. Especially, correct orientation of the position 8 carboxyl group relative to the phenyl group of the phenylalanine residue may be necessary for agonistic activation of the angiotensin receptor complex. Replacement of the aromatic ring on the COOHterminal residue by a nonaromatic group leads to incorrect orientation of the carboxyl group and causes the appearance of antagonist properties. Although the steric effects of the side chain can be modulated by specific interaction of its chemical groups (if any) with the peptide backbone, we found a good correlation between the size of the side chain-e.g., the steric parameter Vy (the van der Waals volume consisting of the C., Cp, and Cy atoms), the conformational properties in the backbone (3J HC.t-NH), and the binding capacities in all compounds tested.

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“…It relied on studies of the conformation of angiotensin II by R. R. Smeby and S. Fermandjian. They had investigated the spatial structure of the molecule by nuclear magnetic resonance (Smeby & Fermandjian 1978). The Takeda structures were aligned with the assumed geometry of the natural substrate and the hypothetical chemical bonds were mapped.…”

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confidence: 99%

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Adam

2005

Studies in History and Philosophy of Science Part C: Studies in

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Appears in Studies in History and Philosophy of Biological and Biomedical Sciences 36 (2005). AbstractRational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent.

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A proposed conformation of isoleucyl5-angiotensin II

Cited by 79 publications

References 10 publications

Studies of Angiotensin‐II Conformations by Circular Dichroism

Studies of Angiotensin‐II Conformations by Circular Dichroism

Studies on angiotensin II and analogs: impact of substitution in position 8 on conformation and activity.

Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

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