Molecular Recognition of Two Endogenous Hormones by the Human Parathyroid Hormone Receptor-1

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2022 Dec 9

PMID 36482086

Authors

Li-Hua Zhao

Qing-Ning Yuan

An-Tao Dai

Xin-Heng He

Chuan-Wei Chen

Chao Zhang

You-Wei Xu

Yan Zhou

Ming-Wei Wang

De-Hua Yang

H Eric Xu

Affiliations

Soon will be listed here.

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.

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References

Gardella T, Vilardaga J . International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors--family B G protein-coupled receptors. Pharmacol Rev. 2015; 67(2):310-37. PMC: 4394688. DOI: 10.1124/pr.114.009464. View

Zhao L, Ma S, Sutkeviciute I, Shen D, Zhou X, de Waal P . Structure and dynamics of the active human parathyroid hormone receptor-1. Science. 2019; 364(6436):148-153. PMC: 6929210. DOI: 10.1126/science.aav7942. View

Gonnelli S, Caffarelli C . Abaloparatide. Clin Cases Miner Bone Metab. 2016; 13(2):106-109. PMC: 5119706. DOI: 10.11138/ccmbm/2016.13.2.106. View

Bilezikian J, Rubin M, Finkelstein J . Parathyroid hormone as an anabolic therapy for women and men. J Endocrinol Invest. 2005; 28(8 Suppl):41-9. View

Ehrenmann J, Schoppe J, Klenk C, Pluckthun A . New views into class B GPCRs from the crystal structure of PTH1R. FEBS J. 2019; 286(24):4852-4860. DOI: 10.1111/febs.15115. View

Srivastava M, Deal C . Osteoporosis in elderly: prevention and treatment. Clin Geriatr Med. 2002; 18(3):529-55. DOI: 10.1016/s0749-0690(02)00022-8. View

Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O . Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596(7873):583-589. PMC: 8371605. DOI: 10.1038/s41586-021-03819-2. View

Sanchez-Garcia R, Gomez-Blanco J, Cuervo A, Carazo J, Sorzano C, Vargas J . DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun Biol. 2021; 4(1):874. PMC: 8282847. DOI: 10.1038/s42003-021-02399-1. View

Roe D, Cheatham 3rd T . PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. J Chem Theory Comput. 2015; 9(7):3084-95. DOI: 10.1021/ct400341p. View

10.

Hattersley G, Dean T, Corbin B, Bahar H, Gardella T . Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology. 2015; 157(1):141-9. PMC: 4701881. DOI: 10.1210/en.2015-1726. View

11.

Zhai X, Mao C, Shen Q, Zang S, Shen D, Zhang H . Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation. Nat Commun. 2022; 13(1):6276. PMC: 9586930. DOI: 10.1038/s41467-022-34009-x. View

12.

Kobayashi K, Kawakami K, Kusakizako T, Miyauchi H, Tomita A, Kobayashi K . Endogenous ligand recognition and structural transition of a human PTH receptor. Mol Cell. 2022; 82(18):3468-3483.e5. DOI: 10.1016/j.molcel.2022.07.003. View

13.

Kir S, White J, Kleiner S, Kazak L, Cohen P, Baracos V . Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature. 2014; 513(7516):100-4. PMC: 4224962. DOI: 10.1038/nature13528. View

14.

Ma S, Shen Q, Zhao L, Mao C, Zhou X, Shen D . Molecular Basis for Hormone Recognition and Activation of Corticotropin-Releasing Factor Receptors. Mol Cell. 2020; 77(3):669-680.e4. DOI: 10.1016/j.molcel.2020.01.013. View

15.

Josephs T, Belousoff M, Liang Y, Piper S, Cao J, Garama D . Structure and dynamics of the CGRP receptor in apo and peptide-bound forms. Science. 2021; 372(6538). DOI: 10.1126/science.abf7258. View

16.

Nishimura Y, Esaki T, Isshiki Y, Furuta Y, Mizutani A, Kotake T . Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist. J Med Chem. 2020; 63(10):5089-5099. DOI: 10.1021/acs.jmedchem.9b01743. View

17.

Quattrocchi E, Kourlas H . Teriparatide: a review. Clin Ther. 2004; 26(6):841-54. DOI: 10.1016/s0149-2918(04)90128-2. View

18.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

19.

Tian C, Kasavajhala K, Belfon K, Raguette L, Huang H, Migues A . ff19SB: Amino-Acid-Specific Protein Backbone Parameters Trained against Quantum Mechanics Energy Surfaces in Solution. J Chem Theory Comput. 2019; 16(1):528-552. DOI: 10.1021/acs.jctc.9b00591. View

20.

Rohou A, Grigorieff N . CTFFIND4: Fast and accurate defocus estimation from electron micrographs. J Struct Biol. 2015; 192(2):216-21. PMC: 6760662. DOI: 10.1016/j.jsb.2015.08.008. View