Structural characterization of peptide hormone/receptor interactions by NMR spectroscopy

Pellegrini, Maria; Mierke, Dale F.

doi:10.1002/(sici)1097-0282(1999)51:3<208::aid-bip4>3.0.co;2-u

Cited by 42 publications

(8 citation statements)

References 121 publications

(65 reference statements)

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“…The structure of AII has been extensively investigated because of its pharmacological importance . Data obtained using several experimental techniques, such as NMR, CD spectroscopy, and X‐ray diffraction , as well as theoretical calculations, suggest that AII has a compact folded structure resulting from the proximity of its amino and carboxy‐terminal extremities. Additionally, a hydrophobic cluster is formed among the Tyr 4 , Ile 5 , and His 6 residues .…”

Section: Resultsmentioning

confidence: 99%

Antiplasmodial activity study of angiotensin II via Ala scan analogs

Silva

Bastos

Torres

et al. 2014

Journal of Peptide Science

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Angiotensin II (AII) as well as analog peptides shows antimalarial activity against Plasmodium gallinaceum and Plasmodium falciparum, but the exact mechanism of action is still unknown. This work presents the solid-phase synthesis and characterization of eight peptides corresponding to the alanine scanning series of AII plus the amide-capped derivative and the evaluation of the antiplasmodial activity of these peptides against mature P. gallinaceum sporozoites. The Ala screening data indicates that the replacement of either the Ile(5) or the His(6) residues causes minor effects on the in vitro antiplasmodial activity compared with AII, i.e. AII (88%), [Ala(6) ]-AII (79%), and [Ala(5) ]-AII (75%). Analogs [Ala(3) ]-AII, [Ala(1) ]-AII, and AII-NH2 showed antiplasmodial activity around 65%, whereas the activity of the [Ala(8) ]-AII, [Ala(7) ]-AII, [Ala(4) ]-AII, and [Ala(2) ]-AII analogs is lower than 45%. Circular dichroism data suggest that AII and the most active analogs adopt a β-fold conformation in different solutions. All AII analogs, except [Ala(4) ]-AII and [Ala(8) ]-AII, show contractile responses and interact with the AT1 receptor, [Ala(5) ]-AII and [Ala(6) ]-AII. In conclusion, this approach is helpful to understand the contribution of each amino acid residue to the bioactivity of AII, opening new perspectives toward the design of new sporozoiticidal compounds.

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Section: Resultsmentioning

confidence: 99%

Antiplasmodial activity study of angiotensin II via Ala scan analogs

Silva

Bastos

Torres

et al. 2014

Journal of Peptide Science

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“…According to some authors , the positions of the residues on the AII molecule determined the degree of pressor activity because of the stabilization of bioactive conformations anchoring, and interactions with the hormone receptor. Results obtained using techniques such as NMR, CD spectroscopy and X‐ray diffraction , in addition to theoretical calculations, suggest that the preferential compact folded structure is adopted. This is thought to be a result of the proximity of its amino and carboxy charged terminal extremities and the interaction between the Tyr 4 and Phe 8 aromatic side chains , mediated by the presence of the His 6 side chain.…”

Section: Discussionmentioning

confidence: 99%

Highly Potential Antiplasmodial Restricted Peptides

et al. 2014

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Malaria is an infectious disease responsible for approximately one million deaths annually. The antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and P. falciparum have recently been reported. To evaluate antiplasmodial activity, we synthesized five angiotensin II-restricted analogs containing disulfide bridges. To accomplish this, peptides containing two inserted amino acid residues (cysteine) were synthesized by the Fmoc solid-phase method, purified by liquid chromatography, and characterized by mass spectrometry. Conformational studies were performed by circular dichroism. The results indicated that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. Results showed that the insertion position must be selected, to preserve the hydrophobic interactions between the non-polar residues, as this affects antiplasmodial activity. The circular dichroism studies suggested that the active analogs as well as the native angiotensin II adopt a β-turn conformation in different solutions. This approach provided insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.

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“…For peptide ligand–receptor interactions, there are three general approaches that can be utilized to extract structural information [4]: a peptide (ligand)‐based approach, a receptor‐based approach, and approaches that target the ligand–receptor complex. In many systems of biological importance, structural characterization of the receptor, and peptide–receptor complexes, is extremely difficult.…”

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confidence: 99%

On the molecular basis of the recognition of angiotensin II (AII)

Tzakos

Bonvin²,

Troganis

et al. 2003

European Journal of Biochemistry

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The high-resolution 3D structure of the octapeptide hormone angiotensin II (AII) in aqueous solution has been obtained by simulated annealing calculations, using highresolution NMR-derived restraints. After final refinement in explicit water, a family of 13 structures was obtained with a backbone RMSD of 0.73 ± 0.23 Å . AII adopts a fairly compact folded structure, with its C-terminus and N-terminus approaching to within 7.2 Å of each other. The side chains of Arg2, Tyr4, Ile5 and His6 are oriented on one side of a plane defined by the peptide backbone, and the Val3 and Pro7 are pointing in opposite directions. The stabilization of the folded conformation can be explained by the stacking of the Val3 side chain with the Pro7 ring and by a hydrophobic cluster formed by the Tyr4, Ile5 and His6 side chains. Comparison between the NMR-derived structure of AII in aqueous solution and the refined crystal structure of the complex of AII with a high-affinity mAb (Fab131) [Garcia, K.C., Ronco, P.M., Verroust, P.J., Brunger, A.T., Amzel, L.M. (1992) Science 257, 502-507] provides important quantitative information on two common structural features: (a) a U-shaped structure of the Tyr4-Ile5-His6-Pro7 sequence, which is the most immunogenic epitope of the peptide, with the Asp1 side chain oriented towards the interior of the turn approaching the C-terminus; (b) an Asxturn-like motif with the side chain aspartate carboxyl group hydrogen-bonded to the main chain NH group of Arg2. It can be concluded that small rearrangements of the epitope 4-7 in the solution structure of AII are required by a mean value of 0.76 ± 0.03 Å for structure alignment and 1.27 ± 0.02 Å for sequence alignment with the X-ray structure of AII bound to the mAb Fab131. These data are interpreted in terms of a biological ÔnucleusÕ conformation of the hormone in solution, which requires a limited number of structural rearrangements for receptor-antigen recognition and binding.Keywords: angiotensin II; monoclonal antibody; NMR; peptide structure; VIb turn.Angiotensin II (AII), the main effector octapeptide hormone (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) of the renin-angiotesin system [1], exerts a variety of actions on different target organs via specific receptors designated AT 1 and AT 2 [2,3]. Most of the known physiological effects of AII have been attributed to AT 1 , e.g. vasoconstriction, aldosterone release, renal sodium reabsorption, as well as central osmoregulatory actions, including the release of pituitary hormones into the circulation and growth stimulation in various cell types. These effects constitute the role of angiotensin peptides as neuromodulators/neurotransmitters in the brain. Because of the variety of biological and physiological actions of AII in various tissues, intensive research is required to determine the structural features of this phylogenetic hormone. This should provide the structural basis for the biological pathway of conformationinformation-transformation.For peptide ligand-receptor interactions, there are three genera...

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Structural characterization of peptide hormone/receptor interactions by NMR spectroscopy

Cited by 42 publications

References 121 publications

Antiplasmodial activity study of angiotensin II via Ala scan analogs

Antiplasmodial activity study of angiotensin II via Ala scan analogs

Highly Potential Antiplasmodial Restricted Peptides

On the molecular basis of the recognition of angiotensin II (AII)

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