Structural transition of human PTH1R revealed distinct molecular recognition and molecular switch for sustainable activation

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  • Kazuhiro Kobayashi
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Kawakami Kouki
    Grad. Sch. of Pharmacol. Sci. & Fac. of Pharmaceut. Sci, The Tohoku University
  • Kusakizako Tshukasa
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Gono Hirotake
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Tomita Atsuhiro
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Kobayashi Kan
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Shihoya Wataru
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo
  • Yamashita Keitaro
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo MRC laboratory of of Mol. Biol.
  • Nishizawa Tomohiro
    Grad. Sci. of Med. Life Sci.. The Yokohama City Univ.
  • Kato Hideaki
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo Grad. sch. of Arts and sci., Coll. of Arts and sci., The Univ. of Tokyo
  • Inoue Asuka
    Grad. Sch. of Pharmacol. Sci. & Fac. of Pharmaceut. Sci, The Tohoku University
  • Nureki Osamu
    Dept. of Biol. Sci., Grad. Sch. of Sci., The Univ. of Tokyo

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Other Title
  • PTH1Rの構造多形から明らかになったリガンド認識における分子相互基盤と持続的受容体活性化メカニズム

Description

<p>Parathyroid hormone receptor 1 (PTH1R) is a class B G-protein-coupled receptor (GPCR), consisting of extracellular domain (ECD) and transmembrane domain (TMD). PTH1R is activated by two endogenous peptide hormones called PTH and PTHrP. These hormones share similar sequences and activate the stimulatory G-protein (Gs) signaling pathway but show different physiological functions by the differences in the ligand dissociation kinetics. However, the structural basis for ligand recognition and ligand kinetics remains elusive.</p><p>We revealed the activated PTH1R structure binding the two</p><p>endogenous hormones, respectively. The structures and mutagenesis revealed distinct molecular recognition for each ligand and conserved active mechanism of PTH1R. Moreover, these structures elucidate molecular switch toggling signaling periods, responsible for the different pharmacological effects. Furthermore, we revealed five distinct structures PTH-PTH1R-Gs toward inactive transition. These sequential structures and molecular dynamics simulations revealed that an unwinding middle region of PTH induces PTH dissociating from PTH1R. This is the first GPCR structure that suggests the ECD allosterically modulates the activation of the receptor. Our structure provides structural insight for a different signal duration and another strategy for drag development for fine-tuning a duration of the receptor activation.</p>

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