title: Purinergic P2X receptors: structural models and analysis of ligand-target interaction.
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.
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy. Electronic address: diego.dalben@unicam.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Dal Ben
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Lambertucci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
authors.forename: Ajiroghene
authors.initials: A
authors.lastname: Thomas
authors.affiliation: School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Volpini
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001393:Azoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058911:Purinergic P2X Receptor Agonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D058469:Receptors, Purinergic P2X / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015027:Zebrafish
chemical_list: C470346:A-317491; D000880:Anthraquinones; D001393:Azoles; D006146:Guanidines; D008024:Ligands; D010636:Phenols; D011083:Polycyclic Compounds; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate; C004711:dicyandiamido
keywords: Molecular modelling; Nucleotides; P2X receptor agonists; P2X receptor antagonists; P2X receptors; Purinergic receptors