[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitleAllosteric modulation and biased signalling at free fatty acid receptor 2.
Journal, issue, pagesNature, Vol. 643, Issue 8074, Page 1428-1438, Year 2025
Publish dateJun 18, 2025
AuthorsXuan Zhang / Abdul-Akim Guseinov / Laura Jenkins / Alice Valentini / Sara Marsango / Katrine Schultz-Knudsen / Trond Ulven / Elisabeth Rexen Ulven / Irina G Tikhonova / Graeme Milligan / Cheng Zhang /
PubMed AbstractFree 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 ...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 disorders. 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 microswitch 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 G versus G 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.
External linksNature / PubMed:40533560 / PubMed Central
MethodsEM (single particle)
Resolution3.06 - 3.3 Å
Structure data

45732

9clw

EMDB-45732, PDB-9clw:
Cryo-EM structure of Gq-coupled FFA2 in complex with TUG-1375 and 4-CMTB
Method: EM (single particle) / Resolution: 3.19 Å

45738

9cm3

EMDB-45738, PDB-9cm3:
Cryo-EM structure of Gq-coupled FFA2 in complex with TUG-1375 and compound 187
Method: EM (single particle) / Resolution: 3.06 Å

45743

9cm7

EMDB-45743, PDB-9cm7:
Cryo-EM structure of Gi-coupled FFA2 in complex with TUG-1375 and AZ-1729
Method: EM (single particle) / Resolution: 3.29 Å

49745

9ns9

EMDB-49745, PDB-9ns9:
Cryo-EM structure of Gi-coupled FFA2 in complex with TUG-1375 and compound 187
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-9UJ:
(2R,4R)-2-(2-chlorophenyl)-3-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]carbonyl-1,3-thiazolidine-4-carboxylic acid

PDB-1lyc:
The impact of the physical and chemical enviroment on the molecular structure of Coprinus cinereus peroxidase

ChemComp-CLR:
CHOLESTEROL

ChemComp-PLM:
PALMITIC ACID

PDB-1azc:
STRUCTURE OF APO-AZURIN FROM ALCALIGENES DENITRIFICANS AT 1.8 ANGSTROMS RESOLUTION

PDB-1azb:
STRUCTURE OF APO-AZURIN FROM ALCALIGENES DENITRIFICANS AT 1.8 ANGSTROMS RESOLUTION

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / agonist

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more