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Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.

Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, Ohta N, Selent J, Bosnyak S, Jones ES, Gerothanassis IP, Tamura M, Widdop RE, Tzakos AG - ACS Chem. Biol. (2014)

Bottom Line: This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target.We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions.Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.

ABSTRACT
GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.

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Related in: MedlinePlus

Structure of [Y]6-AII in complex with AT1R (a) and AT2R(b). [Y]6-AII is shown in yellow stick and surface, andunconserved regions in AT1R and AT2R are shown in red stick and surfaces.Red dashed lines correspond to hydrogen bonds, and green dashed linesto hydrophobic contacts. Residues depicted in blue stick were mutatedfor validation of the binding mode.
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fig4: Structure of [Y]6-AII in complex with AT1R (a) and AT2R(b). [Y]6-AII is shown in yellow stick and surface, andunconserved regions in AT1R and AT2R are shown in red stick and surfaces.Red dashed lines correspond to hydrogen bonds, and green dashed linesto hydrophobic contacts. Residues depicted in blue stick were mutatedfor validation of the binding mode.

Mentions: In order toassess the origin of the highest selectivity of the [Y]6-AII analogue to the AT2R over the AT1R, the relevant analogue wasdocked into the two receptors (Figure 4). Residuesthat interact with the [Y]6-AII analogue in both receptors(Supplementary Figure S7) are also listedin Supplementary Table S6 containing theirresidue ID as well as the corresponding Ballesteros-Weinstein numbering.22


Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.

Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, Ohta N, Selent J, Bosnyak S, Jones ES, Gerothanassis IP, Tamura M, Widdop RE, Tzakos AG - ACS Chem. Biol. (2014)

Structure of [Y]6-AII in complex with AT1R (a) and AT2R(b). [Y]6-AII is shown in yellow stick and surface, andunconserved regions in AT1R and AT2R are shown in red stick and surfaces.Red dashed lines correspond to hydrogen bonds, and green dashed linesto hydrophobic contacts. Residues depicted in blue stick were mutatedfor validation of the binding mode.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374176&req=5

fig4: Structure of [Y]6-AII in complex with AT1R (a) and AT2R(b). [Y]6-AII is shown in yellow stick and surface, andunconserved regions in AT1R and AT2R are shown in red stick and surfaces.Red dashed lines correspond to hydrogen bonds, and green dashed linesto hydrophobic contacts. Residues depicted in blue stick were mutatedfor validation of the binding mode.
Mentions: In order toassess the origin of the highest selectivity of the [Y]6-AII analogue to the AT2R over the AT1R, the relevant analogue wasdocked into the two receptors (Figure 4). Residuesthat interact with the [Y]6-AII analogue in both receptors(Supplementary Figure S7) are also listedin Supplementary Table S6 containing theirresidue ID as well as the corresponding Ballesteros-Weinstein numbering.22

Bottom Line: This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target.We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions.Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.

ABSTRACT
GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.

Show MeSH
Related in: MedlinePlus