| Structural highlights
1bl1 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[PTHR1_HUMAN] Chondrodysplasia, Blomstrand type;Dental ankylosis;Eiken syndrome;Metaphyseal chondrodysplasia, Jansen type;Enchondromatosis. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] The disease is caused by mutations affecting the gene represented in this entry.[6] The disease may be caused by mutations affecting the gene represented in this entry.[7] [8] The disease is caused by mutations affecting the gene represented in this entry.[9] The disease is caused by mutations affecting the gene represented in this entry.
Function
[PTHR1_HUMAN] This is a receptor for parathyroid hormone and for parathyroid hormone-related peptide. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatidylinositol-calcium second messenger system.[10] [11]
Publication Abstract from PubMed
A 31 amino acid fragment of the extracellular N-terminus of the human G-protein coupled receptor for parathyroid hormone (PTH1R) has been structurally characterized by NMR and molecular dynamics simulations. The fragment PTH1R[168-198] includes residues 173-189, shown by photoaffinity cross-linking to be a contact domain with position 13 of parathyroid hormone (PTH). The structure of PTH1R[168-198], determined in a micellar solution of dodecylphosphocholine to mimic the membrane environment, consists of three alpha-helices, separated by a well-defined turn and a flexible region. The topological orientation of PTH1R[168-198] was determined from nitroxide-radical induced relaxation of NMR signals utilizing 5- and 16-doxylstearic acid. The C-terminal helix (residues 190-196), consisting of seven amino acids of the first transmembrane domain, is very hydrophobic and embedded in the lipid core. This helix is preceded by a well-defined turn, forming an approximate 90 degrees bend, placing the other helices (residues 169-176 and 180-189), both of which are amphipathic, on the surface of the micelle. In this orientation, many hydrophilic residues of the receptor, including Glu177, Arg179, Arg181, Glu182, Asp185, and Arg186, are projecting toward the solvent available to form complementary Coulombic interactions with the polar residues of the principal binding domain of the ligand (e.g., Arg25, Lys26, Lys27, Asp30, and His32). Given that the binding domain of PTH adopts an amphipathic alpha-helix which lies on the membrane, we visualize ligand binding as a two stage process involving a nonspecific hydrophobic interaction of amphipathic helices with the membrane, followed by two-dimensional diffusion leading to highly specific, ligand-receptor interaction.
Binding domain of human parathyroid hormone receptor: from conformation to function.,Pellegrini M, Bisello A, Rosenblatt M, Chorev M, Mierke DF Biochemistry. 1998 Sep 15;37(37):12737-43. PMID:9737850[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schipani E, Kruse K, Juppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995 Apr 7;268(5207):98-100. PMID:7701349
- ↑ Schipani E, Langman CB, Parfitt AM, Jensen GS, Kikuchi S, Kooh SW, Cole WG, Juppner H. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med. 1996 Sep 5;335(10):708-14. PMID:8703170
- ↑ Schipani E, Jensen GS, Pincus J, Nissenson RA, Gardella TJ, Juppner H. Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia. Mol Endocrinol. 1997 Jun;11(7):851-8. PMID:9178745
- ↑ Schipani E, Langman C, Hunzelman J, Le Merrer M, Loke KY, Dillon MJ, Silve C, Juppner H. A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen's metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 1999 Sep;84(9):3052-7. PMID:10487664
- ↑ Bastepe M, Raas-Rothschild A, Silver J, Weissman I, Wientroub S, Juppner H, Gillis D. A form of Jansen's metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation. J Clin Endocrinol Metab. 2004 Jul;89(7):3595-600. PMID:15240651 doi:http://dx.doi.org/10.1210/jc.2004-0036
- ↑ Zhang P, Jobert AS, Couvineau A, Silve C. A homozygous inactivating mutation in the parathyroid hormone/parathyroid hormone-related peptide receptor causing Blomstrand chondrodysplasia. J Clin Endocrinol Metab. 1998 Sep;83(9):3365-8. PMID:9745456
- ↑ Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Juppner H, Andrulis IL, Wunder JS, Alman BA. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet. 2002 Mar;30(3):306-10. Epub 2002 Feb 19. PMID:11850620 doi:http://dx.doi.org/10.1038/ng844
- ↑ Rozeman LB, Sangiorgi L, Briaire-de Bruijn IH, Mainil-Varlet P, Bertoni F, Cleton-Jansen AM, Hogendoorn PC, Bovee JV. Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat. 2004 Dec;24(6):466-73. PMID:15523647 doi:http://dx.doi.org/10.1002/humu.20095
- ↑ Duchatelet S, Ostergaard E, Cortes D, Lemainque A, Julier C. Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet. 2005 Jan 1;14(1):1-5. Epub 2004 Nov 3. PMID:15525660 doi:http://dx.doi.org/ddi001
- ↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
- ↑ Pioszak AA, Harikumar KG, Parker NR, Miller LJ, Xu HE. Dimeric arrangement of the parathyroid hormone receptor and a structural mechanism for ligand-induced dissociation. J Biol Chem. 2010 Apr 16;285(16):12435-44. Epub 2010 Feb 19. PMID:20172855 doi:10.1074/jbc.M109.093138
- ↑ Pellegrini M, Bisello A, Rosenblatt M, Chorev M, Mierke DF. Binding domain of human parathyroid hormone receptor: from conformation to function. Biochemistry. 1998 Sep 15;37(37):12737-43. PMID:9737850 doi:http://dx.doi.org/10.1021/bi981265h
|
