title: Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.
abstract: Combining molecular dynamics (MD) in a hydrated phospholipid (DOPC) bilayer, a Monte Carlo search, and synthesis of locked nucleotide analogues, we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y(6) receptor. 2'-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than that for the corresponding flexible 2'-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.
authors.affiliation: NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892. USA. stefanoc@mail.nih.gov
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.forename: Bhalchandra V
authors.initials: BV
authors.lastname: Joshi
authors.forename: Savitri
authors.initials: S
authors.lastname: Maddileti
authors.forename: Liaman
authors.initials: L
authors.lastname: Mamedova
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gonzalez-Moa
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008024:Ligands; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate