The structure of human parathyroid hormone‐related protein(1–34) in near‐physiological solution

Weidler, Marcus; Marx, Ute C.; Seidel, G.; Schäfer, Wolfgang; Hoffmann, Eike; Esswein, A.; Rösch, Paul

doi:10.1016/s0014-5793(98)01658-5

Cited by 28 publications

(16 citation statements)

References 51 publications

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“…The peptides bind to the ECD as amphipathic ␣-helices that contact the hydrophobic groove in the ECD, consistent with NMR solution structures of the isolated peptides that showed ␣-helical structure in the 15-34 fragments of the ligands (42,43). Two of the three invariant residues in the 15-34 fragments, Arg-20Ј and Leu-24Ј, anchor the interaction with the ECD.…”

Section: Discussionsupporting

confidence: 76%

Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

Pioszak

Parker

Gardella

et al. 2009

Journal of Biological Chemistry

139

150

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Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic ␣-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally "unwound." The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECDbinding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics. The parathyroid hormone receptor (PTH1R)3 is a class B G protein-coupled receptor (GPCR) that transduces signals from two related signaling molecules that have distinct functions in biology: parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) (Ref. 1; reviewed in Ref. 2). PTH is an 84-amino acid polypeptide endocrine hormone that is produced by the parathyroid glands and secreted into the circulation in response to low calcium levels (reviewed in Refs. 3-5), to act on bone and kidney cells and thus restore blood calcium to normal levels. In bone, PTH directly stimulates osteoblasts, resulting in bone formation (reviewed in Ref. 6), which in turn activate osteoclasts to induce bone resorption. In the kidney, PTH stimulates the reabsorption of filtered calcium, inhibits the reabsorption of phosphate, and stimulates the synthesis of 1,25-dihydroxyvitamin D3. The paradoxical anabolic/ catabolic actions of PTH on bone can be modulated by exogenous PTH, and provide the molecular basis for the clinical use of PTH as an anabolic therapy for osteoporosis (7). Anabolic PTH therapy requires intermittent administration to minimize bone-resorptive effects, which predominate with sustained administration of PTH. PTHrP is a 141-amino acid polypeptide that was originally isolated as the factor responsible for humoral hyperca...

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Section: Discussionsupporting

confidence: 76%

Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

Pioszak

Parker

Gardella

et al. 2009

Journal of Biological Chemistry

139

150

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“…These structures have been combined with a computer-generated model of the membrane-embedded regions to provide a structural model of the PTH1 receptor [57,58] (see below). most studies find α-helical structure [67][68][69][70][71], specifically an α-helix in the C-terminal region and a smaller α-helical domain in the N-terminal region (Table (1)). The location and size of the helices is generally similar in PTH(1-34) and PTHrP(1-34) ( Table (1), compare line 1 and 5), indicating a similar secondary structure despite the very different primary structures in the C-terminal region.…”

Section: Structural Properties Of Pth Receptorsmentioning

confidence: 99%

Molecular Mechanisms of Ligand Recognition by Parathyroid Hormone 1 (PTH1) and PTH2 Receptors.

Hoare¹,

Usdin²

2001

CPD

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The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) an d tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal alpha-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction). The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.

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“…On the other hand, Wray et al3 and Pellegrini et al14 reported that there was no sound experimental evidence for any significant tertiary structure. The group of Marx et al15–17 reported the presence of very weak interhelical, intramolecular interactions, indicative of a tertiary structure for 1–37, 1–34, 3–37, and 4–34 PTH fragments in TFE‐free solutions. These authors concluded that, due to flexibility of the loop region around Gly12, the relative spatial orientation of the two N‐terminal and C‐terminal helical segments is not fixed, so that no particular tertiary structure is preferred.…”

Section: Introductionmentioning

confidence: 99%

Conformational and biological characterization of human parathyroid hormone hPTH(1–34) analogues containing β‐amino acid residues in positions 17–19

et al. 2003

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The N-terminal 1-34 fragment of parathyroid hormone (PTH) elicits the full spectrum of bone-related biological activities of the intact native sequences. It has been suggested that the structural elements essential for bioactivity are two helical segments located at the N-terminal and C-terminal sequences, connected by hinges or flexible points around positions 12 and 19. In order to assess the relevance of the local conformation around Gly(18) upon biological function, we synthesized and characterized the following human (h) PTH(1-34) analogues containing beta-amino acid residues: [analogues: see text]. Biological activity and binding affinity of analogue I are one order of magnitude lower than those of the parent compound. In analogue II, both binding affinity and biological activity are partially recovered. Analogues III and V have no binding affinity and very low biological activity. Both bioactivity and binding affinity are partially recovered in analogue IV. The conformational properties of the analogues in aqueous solution containing dodecylphosphocholine micelles were studied by CD, 2D-nuclear magnetic resonance and molecular dynamics calculations. The results confirmed the presence in all analogues of two helical segments located at the N-terminal and C-terminal sequences. The insertion of beta-amino acid residues around position 18 does not cause appreciable conformational differences in the five analogues. The differences in biological activity and binding affinity among the five analogues cannot be related to structural differences in the membrane mimetic environment reported in this study. Our results stress the importance of the side-chain functionalities in the sequence 17-19 for biological function.

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The structure of human parathyroid hormone‐related protein(1–34) in near‐physiological solution

Cited by 28 publications

References 51 publications

Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides

Molecular Mechanisms of Ligand Recognition by Parathyroid Hormone 1 (PTH1) and PTH2 Receptors.

Conformational and biological characterization of human parathyroid hormone hPTH(1–34) analogues containing β‐amino acid residues in positions 17–19

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