2. Academic Validation
  3. Allosteric modulation and biased signalling at free fatty acid receptor 2

Allosteric modulation and biased signalling at free fatty acid receptor 2

  • Nature. 2025 Jul;643(8074):1428-1438. doi: 10.1038/s41586-025-09186-6.
Xuan Zhang # 1,  Abdul-Akim Guseinov # 2 3,  Laura Jenkins # 3,  Alice Valentini 4,  Sara Marsango 3,  Katrine Schultz-Knudsen 4,  Trond Ulven 4,  Elisabeth Rexen Ulven 4,  Irina G Tikhonova 5,  Graeme Milligan 6,  Cheng Zhang 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2 School of Pharmacy, Queen's University Belfast, Belfast, UK.
  • 3 Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • 4 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 5 School of Pharmacy, Queen's University Belfast, Belfast, UK. i.tikhonova@qub.ac.uk.
  • 6 Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. graeme.milligan@glasgow.ac.uk.
  • 7 Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. chengzh@pitt.edu.
  • # Contributed equally.
PMID: 40533560 DOI: 10.1038/s41586-025-09186-6
Abstract

Free Fatty Acid Receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that is a primary sensor for short-chain fatty acids produced by gut microbiota. Consequently, FFA2 is a promising drug target for immunometabolic disorders1-4. Here we report cryogenic electronic microscopy structures of FFA2 in complex with two G proteins and three distinct classes of positive allosteric modulators (PAMs), and describe noncanonical activation mechanisms that involve conserved structural features of class A GPCRs. Two PAMs disrupt the E/DRY activation microswitch5 and stabilize the conformation of intracellular loop 2 by binding to lipid-facing pockets near the cytoplasmic side of the receptor. By contrast, the third PAM promotes the separation of transmembrane helices 6 and 7 by interacting with transmembrane helix 6 at the receptor-lipid interface. Molecular dynamic simulations and mutagenesis experiments confirm these noncanonical activation mechanisms. Furthermore, we demonstrate the molecular basis for the Gi versus Gq bias, which is due to distinct conformations of intracellular loop 2 stabilized by different PAMs. These findings provide a framework for the design of tailored GPCR modulators, with implications that extend beyond FFA2 to the broader field of GPCR drug discovery.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z