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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.


Close-up of the binding region between PTH2R and the tuberoinfundibular peptide of 39 residues. The extracellular domain (ECD) in khaki, regions without template in blue, the TM region in white and the tuberoinfundibular peptide of 39 residues (TIP39) in magenta. Residues in the binding interface of TIP39 and the receptor (within 3Å distance of each other) are shown in sticks. Acidic residues are coloured red, polar residues are coloured pink, basic residues are coloured blue and hydrophobic residues are coloured yellow. Residues in TIP39 are labelled in red and residues in the receptor are labelled in gray. A. Interactions of the N-terminus of TIP39 with the TM region. B. Interactions of the C-terminus of TIP39 with the ECD.
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Figure 3: Close-up of the binding region between PTH2R and the tuberoinfundibular peptide of 39 residues. The extracellular domain (ECD) in khaki, regions without template in blue, the TM region in white and the tuberoinfundibular peptide of 39 residues (TIP39) in magenta. Residues in the binding interface of TIP39 and the receptor (within 3Å distance of each other) are shown in sticks. Acidic residues are coloured red, polar residues are coloured pink, basic residues are coloured blue and hydrophobic residues are coloured yellow. Residues in TIP39 are labelled in red and residues in the receptor are labelled in gray. A. Interactions of the N-terminus of TIP39 with the TM region. B. Interactions of the C-terminus of TIP39 with the ECD.

Mentions: The interactions with TIP39 and the receptor are partly defined by polar interactions of basic, acidic and polar residues (shown in blue, red and pink, respectively, in Figure 3), and partly defined by hydrophobic interactions (marked with yellow sticks in Figure 3).


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)

Close-up of the binding region between PTH2R and the tuberoinfundibular peptide of 39 residues. The extracellular domain (ECD) in khaki, regions without template in blue, the TM region in white and the tuberoinfundibular peptide of 39 residues (TIP39) in magenta. Residues in the binding interface of TIP39 and the receptor (within 3Å distance of each other) are shown in sticks. Acidic residues are coloured red, polar residues are coloured pink, basic residues are coloured blue and hydrophobic residues are coloured yellow. Residues in TIP39 are labelled in red and residues in the receptor are labelled in gray. A. Interactions of the N-terminus of TIP39 with the TM region. B. Interactions of the C-terminus of TIP39 with the ECD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 3: Close-up of the binding region between PTH2R and the tuberoinfundibular peptide of 39 residues. The extracellular domain (ECD) in khaki, regions without template in blue, the TM region in white and the tuberoinfundibular peptide of 39 residues (TIP39) in magenta. Residues in the binding interface of TIP39 and the receptor (within 3Å distance of each other) are shown in sticks. Acidic residues are coloured red, polar residues are coloured pink, basic residues are coloured blue and hydrophobic residues are coloured yellow. Residues in TIP39 are labelled in red and residues in the receptor are labelled in gray. A. Interactions of the N-terminus of TIP39 with the TM region. B. Interactions of the C-terminus of TIP39 with the ECD.
Mentions: The interactions with TIP39 and the receptor are partly defined by polar interactions of basic, acidic and polar residues (shown in blue, red and pink, respectively, in Figure 3), and partly defined by hydrophobic interactions (marked with yellow sticks in Figure 3).

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.