Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

Sköld, Christian; Nikiforovich, Gregory V.; Karlén, Anders

doi:10.1016/j.jmgm.2007.08.005

Cited by 8 publications

(6 citation statements)

References 54 publications

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“…Sköld et al [85] explored the binding modes of Ang II and some pseudopeptide analogues at AT 2 R and found two plausible binding modes in agreement with most of the suggested ligand-receptor contact points reported in the literature. Docking calculations, using MacroModel’s Monte Carlo multiple search minimum, showed that the ionic bridge between Phe 8 (carboxyl) of Ang II and Lys215 (AT 1 R) occurred most frequently in the ligand–receptor configurations.…”

Section: Resultsmentioning

confidence: 53%

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

2015

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Abstract:The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.

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Section: Resultsmentioning

confidence: 53%

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

2015

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“…The species-specific difference implies a shift in ligand selectivity during vertebrate evolution. The known amino acid residues responsible for AT2 binding are Ile 14 , Met 128 , Met 138 , Arg 182 , Lys 215 , His 273 , Asp 279 , and Asp 297 in human (Sköld et al, 2008), and 4 out of the 8 residues are identical between eel and human (Fig. 1A).…”

Section: Ligand Selectivity and Binding Characteristics Of Eel At2mentioning

confidence: 99%

“…1A). The conserved residues, namely Met 138 , Lys 215 , and His 273 in the human AT2, target the C-terminal region of Ang II (Sköld et al, 2008), and this explains the flexibility of ligand stimulation of the eel AT2 by Ang II, Ang III, and Ang IV, In situ hybridization of gill section using the AT2 sense probe as a negative control. No specific signals were observed.…”

Section: Ligand Selectivity and Binding Characteristics Of Eel At2mentioning

confidence: 99%

Angiotensin AT2 receptor activates the cyclic-AMP signaling pathway in eel

Wong

Takei

2013

Molecular and Cellular Endocrinology

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“…NMR results of aqueous AngII have also shown AngII in a U-shaped conformation with a turn located between Ile5-His6-Pro7 residues (Spyroulias et al, 2003;Tzakos et al, 2004). In AT 2 -receptor molecular modeling studies, positioning of previously suggested ligandreceptor contacts resulted in AngII adopting a β-extended conformation that extends into the hydrophobic pocket (Boucard et al, 2000;Deraet et al, 2002;Sköld, Nikiforovich, & Karlén, 2008). AngII has been studied using various spectroscopic techniques, but the interpretation of the conformational studies has been inconsistent, most likely from solvent structural dependence, which has led to various structural models for AngII in solution including β pleated sheet, β and γ turns, and other structures (Spyroulias et al, 2003;Tzakos et al, 2004).…”

Section: Introductionmentioning

confidence: 98%

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

DeLeon

Patel

Kuczera

et al. 2012

Journal of Biomolecular Structure and Dynamics

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We present a study of structural analysis and reorientational dynamics of Angiotensin I (AngI) and Angiotensin II (AngII) in aqueous solution. AngI is a decapeptide that acts as a precursor to the octapeptide AngII in the Renin-Angiotensin-Aldosterone system for blood pressure regulation. Experimental structural characterization of these peptides, carried out with circular dichroism and infrared spectroscopy, showed that the angiotensins are mostly disordered but exhibit a measurable population of ordered structures at room temperature. Interestingly, these change from the unordered polyproline-like conformation for AngI to a more compact and ordered conformation for AngII as the length of the peptide is decreased. Anisotropy decay measurements with picosecond time resolution indicate slower overall tumbling and a greater amplitude of internal motion in AngI compared to AngII, consistent with more compact and less flexible structure of the active form of the peptide. To model the microscopic behavior of the peptides, 2-μs molecular dynamics simulation trajectories were generated for AngI and AngII, at 300 K using the OPLS-AA potential and SPC water. The structures sampled in the simulations mostly agree with the experimental results, showing the prevalence of disordered structures, turns, and polyproline helices. Additionally, the computational results predict fewer sampled conformations, tighter side-chain packing and marked increase of Phe8 solvent accessibility upon AngI truncation to AngII. Our combined approach of experiment and extensive computer simulation thus yields new information on the conformational dynamics of the angiotensins, helping provide insight into the structural basis for the potency of AngI relative to AngII.

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Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

Cited by 8 publications

References 54 publications

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

Angiotensin AT2 receptor activates the cyclic-AMP signaling pathway in eel

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

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