Endogenous ligand recognition and structural transition of a human PTH receptor.

GTP-Binding Protein alpha Subunits, Gs / metabolism Humans Ligands Parathyroid Hormone / chemistry Parathyroid Hormone-Related Protein / chemistry Receptor, Parathyroid Hormone, Type 1 / genetics
Class B GPCR GPCR activation cryoelectron microscopy dynamics inactivation ligand kinetics parathyroid hormone type 1 receptor

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
15 09 2022
Historique:
received: 15 06 2021
revised: 07 11 2021
accepted: 11 07 2022
pubmed: 7 8 2022
medline: 21 9 2022
entrez: 6 8 2022
Statut: ppublish

Résumé

Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas PTHrP evokes transient Gs activation with reduced bone-resorption effects. The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation kinetics. Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the presence of PTH or PTHrP at resolutions of 2.8 -4.1 Å. A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. Furthermore, five distinct PTH-bound structures, combined with computational analyses, provide insights into the unique and complex process of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.

Identifiants

DOI: 10.1016/j.molcel.2022.07.003 PMID: 35932760
pubmed: 35932760
pii: S1097-2765(22)00660-8
doi: 10.1016/j.molcel.2022.07.003
pii:
doi:

Substances chimiques

Ligands 0
Parathyroid Hormone 0
Parathyroid Hormone-Related Protein 0
Receptor, Parathyroid Hormone, Type 1 0
GTP-Binding Protein alpha Subunits, Gs EC 3.6.5.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3468-3483.e5

Subventions

Organisme : NCI NIH HHS
ID : R01 CA129325
Pays : United States

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests O.N. is a co-founder and an external director of Curreio Inc.

Auteurs

Kazuhiro Kobayashi (K)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Kouki Kawakami (K)

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.

Tsukasa Kusakizako (T)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Hirotake Miyauchi (H)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Atsuhiro Tomita (A)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Kan Kobayashi (K)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Wataru Shihoya (W)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Keitaro Yamashita (K)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Tomohiro Nishizawa (T)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.

Hideaki E Kato (HE)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan; Komaba Institute for Science, the University of Tokyo, Meguro, Tokyo 153-8505, Japan; FOREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. Electronic address: hekato@bio.c.u-tokyo.ac.jp.

Asuka Inoue (A)

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan. Electronic address: iaska@tohoku.ac.jp.

Osamu Nureki (O)

Department of Biological Sciences, Graduate School of Science, the University of Tokyo, Bunkyo, Tokyo 113-0033, Japan. Electronic address: nureki@bs.s.u-tokyo.ac.jp.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines G hétérotrimériques › Sous-unités alpha des protéines G › Sous-unités alpha Gs des protéines G › Endogenous ligand recognition and structural...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Endogenous ligand recognition and structural...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Ligands › Endogenous ligand recognition and structural...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Hormone parathyroïdienne › Endogenous ligand recognition and structural...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéine apparentée à l'hormone parathyroïdienne › Endogenous ligand recognition and structural...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteurs à l'hormone parathyroïdienne › Récepteur de la parathormone de type 1 › Endogenous ligand recognition and structural...