Abstract
This chapter describes the molecular biology of the parathyroid hormone receptor type 1 (PTHR1), specifically at the level of ligand binding and signal activation mechanisms. It begins with the basic protein architecture of the PTHR1, viewed particularly in the light of the X-ray crystal and cryo-electron microscopy structures that have emerged for several related class B G-protein-coupled receptors. The evolutionary history of the PTHR1 and its ligands is then outlined, from ancient origins in early chordates through the gene rearrangement events that led to the diversified receptor subtypes seen in various vertebrate lineages, as well the possibility for other receptors for C-terminal portions of parathyroid hormone and parathyroid hormone–related protein. Focus then turns to specific mechanisms of binding and activation at the PTHR1, and how new developing concepts of ligand-dependent conformational selectivity, temporal bias, and endosomal signaling are suggesting unique opportunities for new therapeutic ligand development. Disease-causing mutations in the PTHR1 are then discussed in terms of their impact on basic mechanisms, and finally presented are the recent advances in small-molecule ligand discovery for the PTHR1. In all, the chapter aims to sharpen awareness of progress made in defining how the PTHR1 functions and how it might be better targeted for the treatment of bone and mineral metabolism diseases.
Published Version
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