8JR9

Small molecule agonist (PCO371) bound to human parathyroid hormone receptor type 1 (PTH1R)

Summary for 8JR9

• Entry DOI: 10.2210/pdb8jr9/pdb
• EMDB information: 36593
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: class b, gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 158833.09

Authors

Zhao, L.,He, Q.,Yuan, Q.,Gu, Y.,He, X.,Shan, H.,Li, J.,Wang, K.,Li, Y.,Hu, W.,Wu, K.,Shen, J.,Xu, H.E. (deposition date: 2023-06-16, release date: 2023-08-02, Last modification date: 2024-11-06)

Primary citation

Zhao, L.H.,He, Q.,Yuan, Q.,Gu, Y.,He, X.,Shan, H.,Li, J.,Wang, K.,Li, Y.,Hu, W.,Wu, K.,Shen, J.,Xu, H.E.
Conserved class B GPCR activation by a biased intracellular agonist.
Nature, 621:635-641, 2023

PubMed Abstract: Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.

PubMed: 37524305
DOI: 10.1038/s41586-023-06467-w

Experimental method

ELECTRON MICROSCOPY (2.57 Å)