Molecular characterization of the receptor-ligand complex for parathyroid hormone

Molecular models for the interaction of parathyroid hormone (PTH) with its G-protein-coupled receptors (PTH1 and PTH2) have been developed. The proposed ligand-receptor complex is based on experimental data from spectroscopic investigations of the hormone and receptor fragments as well as theoretical structure predictions based on homology analysis with proteins of known structure. From the insight afforded by the models, biochemical and pharmacological observations can be correlated with specific molecular or atomic interactions. The ligand selectivity of PTH2, specifically the lack of binding of His5-containing analogues, can be ascribed to unfavorable steric interactions (the binding pocket is markedly smaller in PTH2 than PTH1) as well as repulsive Coulombic forces between amino acids of like-charge (a positively charged H384 is located in the binding pocket in PTH2). The model of PTH1 suggests that the constitutive activity observed from the incorporation of a positively charged amino acid at position 223, found at the cytoplasmic end of TM2, is caused by a Coulombic attraction to E465, at the cytoplasmic end of TM7, leading to an association of TM2 and TM7 and thereby ligand-free activation. Additionally, a number of important interactions in the ligand-receptor complex are described along with predictions of the pharmacological profile which will result from specific modifications at these sites. In this regard, the models described here allow for atomic insight into the biochemical data currently available and allow targeting of future mutations to probe specific ligand/receptor interactions and thereby further our understanding of the functioning of this important hormone system.