PUBLICATION
Purinergic P2X receptors: Structural models and analysis of ligand-target interaction
- Authors
- Dal Ben, D., Buccioni, M., Lambertucci, C., Marucci, G., Thomas, A., Volpini, R.
- ID
- ZDB-PUB-141203-15
- Date
- 2015
- Source
- European Journal of Medicinal Chemistry 89C: 561-580 (Journal)
- Registered Authors
- Keywords
- Molecular modelling, Nucleotides, P2X receptor agonists, P2X receptor antagonists, P2X receptors, Purinergic receptors
- MeSH Terms
-
- Adenosine Triphosphate/metabolism
- Animals
- Anthraquinones/chemistry
- Anthraquinones/metabolism
- Anthraquinones/pharmacology
- Azoles/chemistry
- Azoles/metabolism
- Azoles/pharmacology
- Binding Sites
- Guanidines/chemistry
- Guanidines/metabolism
- Guanidines/pharmacology
- Humans
- Ligands
- Models, Molecular
- Molecular Conformation
- Phenols/chemistry
- Phenols/metabolism
- Phenols/pharmacology
- Polycyclic Compounds/chemistry
- Polycyclic Compounds/metabolism
- Polycyclic Compounds/pharmacology
- Purinergic P2X Receptor Agonists/chemistry*
- Purinergic P2X Receptor Agonists/metabolism*
- Purinergic P2X Receptor Agonists/pharmacology
- Purinergic P2X Receptor Antagonists/chemistry*
- Purinergic P2X Receptor Antagonists/metabolism*
- Purinergic P2X Receptor Antagonists/pharmacology
- Rats
- Receptors, Purinergic P2X/chemistry*
- Receptors, Purinergic P2X/metabolism*
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 25462266 Full text @ Eur. J. Med. Chem.
Citation
Dal Ben, D., Buccioni, M., Lambertucci, C., Marucci, G., Thomas, A., Volpini, R. (2015) Purinergic P2X receptors: Structural models and analysis of ligand-target interaction. European Journal of Medicinal Chemistry. 89C:561-580.
Abstract
The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping