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Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human.

Caseley EA, Muench SP, Baldwin SA, Simmons K, Fishwick CW, Jiang LH - Bioorg. Med. Chem. Lett. (2015)

Bottom Line: Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity.This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity.Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: bs09e2c@leeds.ac.uk.

No MeSH data available.


Related in: MedlinePlus

Sequence alignment of the first 360 amino acids of the rat and human P2X7 receptors with residues which are within 8 Å of the predicted ligand binding site highlighted in grey. Residues which differ between the two sequences are highlighted in green.
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f0015: Sequence alignment of the first 360 amino acids of the rat and human P2X7 receptors with residues which are within 8 Å of the predicted ligand binding site highlighted in grey. Residues which differ between the two sequences are highlighted in green.

Mentions: As shown in Figure 2B, D and F, the pi-stacking interactions seen between Phe95 and the aromatic rings of the inhibitors are lost in the same site in the rat P2X7 receptor. This provides striking evidence for the essential role of this residue in determining the species-specific activity of these compounds. Sequence alignment of residues within 8 Å of the predicted binding site shows that Phe95 is the only residue which is not conserved between the human and rat receptor located in a region which may interact with the inhibitors (Fig. 3). The importance of this residue is further validated by previous studies which used a human–rat chimeric receptor whereby a leucine replaced Phe at this position in the human P2X7 receptor, greatly reducing the efficacy of these three inhibitors.34,35 Conversely, introducing the L95F mutation into the rat receptor has been shown to have a varied impact on the ability of the compounds described above to inhibit the rat P2X7 receptor.34 SB203580 changes from having no effect at the wild-type receptor to acting as an antagonist of the L95F rat receptor, albeit to a lesser degree than the human receptor. Additionally, the L95F mutation allows KN62 to modestly inhibit responses when lower concentrations of ATP are applied.


Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human.

Caseley EA, Muench SP, Baldwin SA, Simmons K, Fishwick CW, Jiang LH - Bioorg. Med. Chem. Lett. (2015)

Sequence alignment of the first 360 amino acids of the rat and human P2X7 receptors with residues which are within 8 Å of the predicted ligand binding site highlighted in grey. Residues which differ between the two sequences are highlighted in green.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508345&req=5

f0015: Sequence alignment of the first 360 amino acids of the rat and human P2X7 receptors with residues which are within 8 Å of the predicted ligand binding site highlighted in grey. Residues which differ between the two sequences are highlighted in green.
Mentions: As shown in Figure 2B, D and F, the pi-stacking interactions seen between Phe95 and the aromatic rings of the inhibitors are lost in the same site in the rat P2X7 receptor. This provides striking evidence for the essential role of this residue in determining the species-specific activity of these compounds. Sequence alignment of residues within 8 Å of the predicted binding site shows that Phe95 is the only residue which is not conserved between the human and rat receptor located in a region which may interact with the inhibitors (Fig. 3). The importance of this residue is further validated by previous studies which used a human–rat chimeric receptor whereby a leucine replaced Phe at this position in the human P2X7 receptor, greatly reducing the efficacy of these three inhibitors.34,35 Conversely, introducing the L95F mutation into the rat receptor has been shown to have a varied impact on the ability of the compounds described above to inhibit the rat P2X7 receptor.34 SB203580 changes from having no effect at the wild-type receptor to acting as an antagonist of the L95F rat receptor, albeit to a lesser degree than the human receptor. Additionally, the L95F mutation allows KN62 to modestly inhibit responses when lower concentrations of ATP are applied.

Bottom Line: Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity.This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity.Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, University of Leeds, Leeds, UK. Electronic address: bs09e2c@leeds.ac.uk.

No MeSH data available.


Related in: MedlinePlus