Characterization of parathyroid hormone/receptor interactions: Structure of the first extracellular loop

被引:70
作者
Piserchio, A
Bisello, A
Rosenblatt, M
Chorev, M
Mierke, DF
机构
[1] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Div Biol & Med, Providence, RI 02912 USA
[2] Brown Univ, Dept Chem, Providence, RI 02912 USA
[3] Beth Israel Deaconess Med Ctr, Div Bone & Mineral Metab, Charles A Dana & Thorndike Labs, Dept Med, Boston, MA 02215 USA
关键词
D O I
10.1021/bi000196f
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 cx-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.
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页码:8153 / 8160
页数:8
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