Back to Search
Start Over
A molecular switch regulating transcriptional repression and activation of PPARĪ³.
- Source :
-
Nature communications [Nat Commun] 2020 Feb 19; Vol. 11 (1), pp. 956. Date of Electronic Publication: 2020 Feb 19. - Publication Year :
- 2020
-
Abstract
- Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARĪ³) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.
- Subjects :
- Apoproteins chemistry
Apoproteins metabolism
Binding Sites
Co-Repressor Proteins chemistry
Crystallography, X-Ray
HEK293 Cells
Humans
Ligands
Magnetic Resonance Spectroscopy
Mutation
Nuclear Receptor Coactivators chemistry
Nuclear Receptor Coactivators metabolism
PPAR gamma agonists
PPAR gamma genetics
Protein Binding
Protein Conformation
Structure-Activity Relationship
Transcription, Genetic
Benzamides metabolism
Co-Repressor Proteins metabolism
PPAR gamma chemistry
PPAR gamma metabolism
Pyridines metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 32075969
- Full Text :
- https://doi.org/10.1038/s41467-020-14750-x