PTH/PTHrP Receptor Signaling, Allostery, and Structures

Abstract

The parathyroid hormone (PTH) type 1 receptor (PTHR) is the canonical G protein-coupled receptor (GPCR) for PTH and PTH-related protein (PTHrP) and the key regulator of calcium homeostasis and bone turnover. PTHR function is critical for human health to maintain homeostatic control of ionized serum Ca²⁺ levels and has several unusual signaling features, such as endosomal cAMP signaling, that are well-studied but not structurally understood. In this review, we discuss how recently solved high resolution near-atomic structures of hormone-bound PTHR in its inactive and active signaling states and discovery of extracellular Ca²⁺ allosterism shed light on the structural basis for PTHR signaling and function.

Keywords: G protein-coupled receptor; allostery; cAMP; cryo-EM structure; endosomes; parathyroid hormone.