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Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1

Li-hua Zhao1,2, Qing-ning Yuan1, An-tao Dai1,3, Xin-heng He1,2, Chuan-wei Chen4, Chao Zhang5, You-wei Xu1, Yan Zhou1,3, Ming-wei Wang4,6,7, De-hua Yang1,2,3, H. Eric Xu1,2
1 The CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 Research Center for Deepsea Bioresources, Sanya 572025, China
5 School of Pharmacy, Fudan University, Shanghai 201203, China
6 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
7 Department of Chemistry, School of Science, The University of Tokyo, Tokyo 113-0033, Japan
Correspondence to: Li-hua Zhao: zhaolihuawendy@simm.ac.cn, De-hua Yang: dhyang@simm.ac.cn, H. Eric Xu: eric.xu@simm.ac.cn,
DOI: 10.1038/s41401-022-01032-z
Received: 2 October 2022
Accepted: 15 November 2022
Advance online: 8 December 2022

Abstract

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.
Keywords: G protein- coupled receptors; parathyroid hormone; PTH-related peptide; PTH receptor-1; cryo-electron microscopy structure; osteoporosis

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