Allosteric mechanism in the distinctive coupling of Gq and Gs to the parathyroid hormone type 1 receptor

• 成果类型: Article
• 署名作者: Zhang, Xuan; Lee, Ji Young; Pacheco, Jonathan; Sutkeviciute, Ieva; Anitha, Anju Krishnan; Liu, Heng; Singh, Stephanie; Ventura, Carlos; Savransky, Sofya; Khatri, Ashok; Zhang, Cheng; Bahar, Ivet; Vilardaga, Jean-Pierre
• 署名单位: Guangzhou Medical University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; State University of New York (SUNY) System; Stony Brook University; State University of New York (SUNY) System; Stony Brook University; Stony Brook University Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; US Department of Veterans Affairs
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10585
• DOI: 10.1073/pnas.2426178122
• 发表日期: 2025-04-01
• 关键词: (pth)/pth-related peptide receptor; g-proteins; pth; DYNAMICS; kinase; activation

摘要

The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with Gs, we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix alpha 5 of the G alpha subunit controls the stability of the PTH1R complex with the specific G protein, Gs or Gq. Single-cell-level experiments further validate the G protein-selective effects of the PTH binding pose by demonstrating the differential, G protein-dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to Gs or Gq and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.