Research Article

Structure and dynamics of the active human parathyroid hormone receptor-1

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Science  12 Apr 2019:
Vol. 364, Issue 6436, pp. 148-153
DOI: 10.1126/science.aav7942

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Bone-cell regulation, fleshed out

One of many medically relevant G protein–coupled receptors, parathyroid hormone receptor-1 (PTH1R) functions in the control of calcium homeostasis and bone physiology. Zhao et al. used cryo–election microscopy to observe the structure of PTH1R in a complex with a modified form of parathyroid hormone and stimulatory G protein. The structural model helps explain how parathyroid hormone interacts with its receptor and the molecular basis for receptor activation.

Science, this issue p. 148

Abstract

The parathyroid hormone receptor-1 (PTH1R) is a class B G protein–coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo–electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.

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