ISSN:
1573-3904
Keywords:
melanocortin receptor
;
partial least squares regression
;
receptor chimeras
;
thyroliberin
;
TRH
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Summary We found recently that thyrotropin-relasing hormone (TRH) acts as a selective agonist on the melanocortin MC1 receptor. While the TRH was capable of fully activating the MC1 receptor, it did not interact with any of the other MSH peptide binding G-protein coupled melanocortin receptor subtypes MC3–5. The MC1 receptor is a promising target for the development of anti-inflammatory and immuno-modulatory drugs, and it was of wide interest to explore the binding site of the TRH in this receptor. Here we have investigated the binding of TRH to MC1/MC3 chimeric receptors and used a partial least squares (PLS) modelling approach for the data evaluation. Statistically valid PLS models (R2=0.80; Q2=0.66) were obtained explaining the contribution of the amino acid sequence parts of the receptor chimeras for the binding of TRH. By using the variable importances in the projection (VIPs) deduced from the PLS-model, it was revealed that the trnsmembrane (TM) regions TM1 and TM2/TM3 contribute the most to the TRH binding. The TM6/TM7 also had a significant influence on the binding. Moreover, it was revealed that an interaction between TM1 and TM6/TM7 of the receptor contributed to the binding of TRH. The data are in full agreement with a 3D model of a TRH peptide and MC1 receptor complex and validates the location of the TRH ligand binding pocket between the TM1, TM2 and TM7 of the receptor.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02447861
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