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The Parathyroid Hormone Receptor Type 1

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Osteoporosis

Part of the book series: Contemporary Endocrinology ((COE))

Abstract

This chapter describes the molecular and structural properties of the parathyroid hormone receptor type 1 (PTHR1), with emphasis on mechanisms of ligand binding and signal activation, as well as therapeutic applications. The basic protein architecture and mechanistic actions of the PTHR1 can now be viewed in light of the recently reported X-ray crystal and cryo-EM structures obtained for this receptor, which provide insights at an atomic level of resolution. These new structures confirm that the PTHR1 adopts an overall protein topology similar to that seen in peptide hormone-binding G protein-coupled receptors that comprise the class B GPCR subgroup and that it furthermore utilizes a similar basic mechanism of ligand binding and activation. Pharmacologic studies on the PTHR1 have led to the concept that structurally distinct PTH and PTHrP ligands and analogs can bind with altered affinities to different PTHR1 conformations to thus induce different types of signaling responses, including prolonged cAMP responses from endosomes. These distinct modes of action suggest potential new paths to explore for therapeutic ligand development. A number of diseases are linked to mutations in the genes for the PTHR1 or its ligands, PTH and PTHrP, and the evolving approaches for developing new PTHR1 ligands, including small molecules, may lead to new modes of treatment for such diseases.

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    Thomas J. Gardella

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Gardella, T.J. (2020). The Parathyroid Hormone Receptor Type 1. In: Leder, B., Wein, M. (eds) Osteoporosis. Contemporary Endocrinology. Humana, Cham. https://doi.org/10.1007/978-3-319-69287-6_16

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