title: Characterization of parathyroid hormone/receptor interactions: structure of the first extracellular loop.
abstract: The structural features of the first extracellular loop (ECL1) of the parathyroid hormone receptor (PTH1R) in the presence of dodecylphosphocholine micelles have been determined using high-resolution NMR techniques. The structure of the receptor fragment, PTH1R(241-285), includes three alpha-helices for residues 241-244, 256-264, and 275-284. The first and third correspond to the end and the beginning of transmembrane helices 2 and 3, respectively. Centrally located in the second helix is L(261), found to cross-link to Lys(27) of parathyroid hormone, PTH(1-34) [Greenberg, Z., Bisello, A., Mierke, D. F., Rosenblatt, M., and Chorev, M. (2000) Biochemistry 39, 8142-8152]. On the basis of nitroxide radical-induced relaxation studies, the central helix is found to associate with the surface of the membrane mimetic. These data, in conjunction with previous results indicating a preference of PTH for the lipid surface, suggest a membrane-associated pathway for the initial recognition and binding of PTH to its G-protein-coupled receptor. Using the structural features of ECL1 as determined here, along with the structure of the PTH(1-34), the intermolecular interactions consistent with the contact point between L(261)(receptor)-Lys(27)(ligand) are identified.
authors.affiliation: Department of Chemistry, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: A
authors.initials: A
authors.lastname: Piserchio
authors.forename: A
authors.initials: A
authors.lastname: Bisello
authors.forename: M
authors.initials: M
authors.lastname: Rosenblatt
authors.forename: M
authors.initials: M
authors.lastname: Chorev
authors.forename: D F
authors.initials: DF
authors.lastname: Mierke
mesh_terms: D000595:Amino Acid Sequence; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry; D008823:Micelles; D008956:Models, Chemical; D008958:Models, Molecular; D010281:Parathyroid Hormone / Q000737:chemistry* / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D011487:Protein Conformation; D018016:Receptors, Parathyroid Hormone / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D008823:Micelles; D010281:Parathyroid Hormone; D018016:Receptors, Parathyroid Hormone; D010767:Phosphorylcholine; C028810:dodecylphosphocholine