Limits...
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.


Alignments. Black shaded residues are identical and grey shaded residues are similar according to PAM250 similarity matrix. A: Alignment between PTH2R and the templates used for homology modelling; thick border box - extracellular domain; thin border box - transmembrane region; no box - intracellular domain. B: Alignment of tuberoinfundibular peptide of 39 residues (TIP39), parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP). The amphipatic nature of the peptides is visible through the pattern of conserved hydrophobic residues in the C-terminal portion of the alignment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2991341&req=5

Figure 1: Alignments. Black shaded residues are identical and grey shaded residues are similar according to PAM250 similarity matrix. A: Alignment between PTH2R and the templates used for homology modelling; thick border box - extracellular domain; thin border box - transmembrane region; no box - intracellular domain. B: Alignment of tuberoinfundibular peptide of 39 residues (TIP39), parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP). The amphipatic nature of the peptides is visible through the pattern of conserved hydrophobic residues in the C-terminal portion of the alignment.

Mentions: Figure 1A shows the alignment of PTH2R and the templates used in the modelling. The ECD shows 50% residue identity while the TM region shows only 11%. Seven residues form the linker region between the ECD and the TM region. It is noticeable that ECL1 (residues 179 - 205 in the mature chain of PTH2R) is longer than in the template and thereby lacks a structural template. ECL2 (residues 276 - 285) which contains the conserved disulfide in the GPCR super-family is shorter than in β1R, which contain a helical region.


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)

Alignments. Black shaded residues are identical and grey shaded residues are similar according to PAM250 similarity matrix. A: Alignment between PTH2R and the templates used for homology modelling; thick border box - extracellular domain; thin border box - transmembrane region; no box - intracellular domain. B: Alignment of tuberoinfundibular peptide of 39 residues (TIP39), parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP). The amphipatic nature of the peptides is visible through the pattern of conserved hydrophobic residues in the C-terminal portion of the alignment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Alignments. Black shaded residues are identical and grey shaded residues are similar according to PAM250 similarity matrix. A: Alignment between PTH2R and the templates used for homology modelling; thick border box - extracellular domain; thin border box - transmembrane region; no box - intracellular domain. B: Alignment of tuberoinfundibular peptide of 39 residues (TIP39), parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP). The amphipatic nature of the peptides is visible through the pattern of conserved hydrophobic residues in the C-terminal portion of the alignment.
Mentions: Figure 1A shows the alignment of PTH2R and the templates used in the modelling. The ECD shows 50% residue identity while the TM region shows only 11%. Seven residues form the linker region between the ECD and the TM region. It is noticeable that ECL1 (residues 179 - 205 in the mature chain of PTH2R) is longer than in the template and thereby lacks a structural template. ECL2 (residues 276 - 285) which contains the conserved disulfide in the GPCR super-family is shorter than in β1R, which contain a helical region.

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.