title: Molecular modeling of the human P2Y14 receptor: A template for structure-based design of selective agonist ligands.
abstract: The P2Y14 receptor (P2Y14R) is a Gi protein-coupled receptor that is activated by uracil nucleotides UDP and UDP-glucose. The P2Y14R structure has yet to be solved through X-ray crystallography, but the recent agonist-bound crystal structure of the P2Y12R provides a potentially suitable template for its homology modeling for rational structure-based design of selective and high-affinity ligands. In this study, we applied ligand docking and molecular dynamics refinement to a P2Y14R homology model to qualitatively explain structure-activity relationships of previously published synthetic nucleotide analogues and to probe the quality of P2Y14R homology modeling as a template for structure-based design. The P2Y14R model supports the hypothesis of a conserved binding mode of nucleotides in the three P2Y12-like receptors involving functionally conserved residues. We predict phosphate group interactions with R253(6.55), K277(7.35), Y256(6.58) and Q260(6.62), nucleobase (anti-conformation) π-π stacking with Y102(3.33) and the role of F191(5.42) as a means for selectivity among P2Y12-like receptors. The glucose moiety of UDP-glucose docked in a secondary subpocket at the P2Y14R homology model. Thus, P2Y14R homology modeling may allow detailed prediction of interactions to facilitate the design of high affinity, selective agonists as pharmacological tools to study the P2Y14R.
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810, USA.
authors: Kevin
authors: K
authors: Trujillo
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810, USA.
authors: Silvia
authors: S
authors: Paoletta
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810, USA.
authors: Evgeny
authors: E
authors: Kiselev
authors: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810, USA. Electronic address: kajacobs@helix.nih.gov.
authors: Kenneth A
authors: KA
authors: Jacobson
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000737:chemistry* / Q000378:metabolism*; D012266:Ribose / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C518528:P2Y14 receptor, human; D010710:Phosphates; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D012266:Ribose; D005947:Glucose
keywords: Docking; G protein-coupled receptor; Homology modeling; P2Y(14) receptor; Uracil nucleotides