TY - JOUR AU - Zhao Li-hua AU - Yuan Qing-ning AU - Dai An-tao AU - He Xin-heng AU - Chen Chuan-wei AU - Zhang Chao AU - Xu You-wei AU - Zhou Yan AU - Wang Ming-wei AU - Yang De-hua AU - Xu H. Eric PY - 2023 TI - Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1 JF - Acta Pharmacologica Sinica; Vol 44, No 6 (June 2023): Acta Pharmacologica Sinica Y2 - 2023 KW - N2 - 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. UR - http://www.chinaphar.com/article/view/10840