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Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues.

Abraham-Nordling M, Persson B, Nordling E - BMC Res Notes (2010)

Bottom Line: The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides.A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Mirna.Abraham.Nordling@ki.se.

ABSTRACT

Background: We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.

Findings: In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation.

Conclusions: A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

No MeSH data available.


Interactions between PTH2R and the investigated hormones. Tuberoinfundibular peptide of 39 residues in magenta, parathyroid hormone in pink and parathyroid related protein in yellow. A. The central interaction of Asp7, Ile5, His5 with His396 of TM helix 7 of the receptor. B. Trp25, 23 and Phe23 is shown with interacting residues Ile34, Gln37, Ile38, Val41 and Ile90 in the ECD of the receptor.
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Figure 4: Interactions between PTH2R and the investigated hormones. Tuberoinfundibular peptide of 39 residues in magenta, parathyroid hormone in pink and parathyroid related protein in yellow. A. The central interaction of Asp7, Ile5, His5 with His396 of TM helix 7 of the receptor. B. Trp25, 23 and Phe23 is shown with interacting residues Ile34, Gln37, Ile38, Val41 and Ile90 in the ECD of the receptor.

Mentions: Primary differences between the hormones TIP39 and PTH that bind and at least partially activate PTH2R and PTHrP which lacks binding affinity, include Phe23 in PTHrP which corresponds to a Trp in the agonistic peptides, interacting with a mainly hydrophobic environment consisting of residues Ile10, Gln13, Ile14, Val17 and Ile66 in the ECD (see Figure 4B), and His5 corresponding to Asp in TIP39 and Leu in PTH and which is placed in the vicinity of His396 of TM helix 7 (see Figure 4A).


Model of the complex of Parathyroid hormone-2 receptor and Tuberoinfundibular peptide of 39 residues.

Abraham-Nordling M, Persson B, Nordling E - BMC Res Notes (2010)

Interactions between PTH2R and the investigated hormones. Tuberoinfundibular peptide of 39 residues in magenta, parathyroid hormone in pink and parathyroid related protein in yellow. A. The central interaction of Asp7, Ile5, His5 with His396 of TM helix 7 of the receptor. B. Trp25, 23 and Phe23 is shown with interacting residues Ile34, Gln37, Ile38, Val41 and Ile90 in the ECD of the receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991341&req=5

Figure 4: Interactions between PTH2R and the investigated hormones. Tuberoinfundibular peptide of 39 residues in magenta, parathyroid hormone in pink and parathyroid related protein in yellow. A. The central interaction of Asp7, Ile5, His5 with His396 of TM helix 7 of the receptor. B. Trp25, 23 and Phe23 is shown with interacting residues Ile34, Gln37, Ile38, Val41 and Ile90 in the ECD of the receptor.
Mentions: Primary differences between the hormones TIP39 and PTH that bind and at least partially activate PTH2R and PTHrP which lacks binding affinity, include Phe23 in PTHrP which corresponds to a Trp in the agonistic peptides, interacting with a mainly hydrophobic environment consisting of residues Ile10, Gln13, Ile14, Val17 and Ile66 in the ECD (see Figure 4B), and His5 corresponding to Asp in TIP39 and Leu in PTH and which is placed in the vicinity of His396 of TM helix 7 (see Figure 4A).

Bottom Line: The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides.A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Mirna.Abraham.Nordling@ki.se.

ABSTRACT

Background: We aim to propose interactions between the parathyroid hormone-2 receptor (PTH2R) and its ligand the tuberoinfundibular peptide of 39 residues (TIP39) by constructing a homology model of their complex. The two related peptides parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) are compared with the complex to examine their interactions.

Findings: In the model, the hydrophobic N-terminus of TIP39 is buried in a hydrophobic part of the central cavity between helices 3 and 7. Comparison of the peptide sequences indicates that the main discriminator between the agonistic peptides TIP39 and PTH and the inactive PTHrP is a tryptophan-phenylalanine replacement. The model indicates that the smaller phenylalanine in PTHrP does not completely occupy the binding site of the larger tryptophan residue in the other peptides. As only TIP39 causes internalisation of the receptor and the primary difference being an aspartic acid in position 7 of TIP39 that interacts with histidine 396 in the receptor, versus isoleucine/histidine residues in the related hormones, this might be a trigger interaction for the events that cause internalisation.

Conclusions: A model is constructed for the complex and a trigger interaction for full agonistic activation between aspartic acid 7 of TIP39 and histidine 396 in the receptor is proposed.

No MeSH data available.