Year: 2020
Type: article
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 (PPARγ) 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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: National Science Foundation, U.S. Department of Energy, U.S. Department of Health and Human Services, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1229526393, G1286251239, G1568510961, G1804828992, G1831385526, REU Site: SURFing the Interface between Chemistry and Biology, G2280469983, G2300450775, G2371548206, G239196684, G2393997808, G262532246, G303061748, G315621713, G3488436650, G3629260272, G4235786860, G4280418065, G4581610328, Molecular Characterization of Novel Insulin Sensitizers, G4654690619, G4908923434, G495301720, G498139845, G5570207115, G628751139, G6550344761, Structural Analysis of Corepressor Binding to PPARγ, G7083997402, G7283024673, G7306125919, G7313278570, A Synchroton Radiation Structural Biology Resource, G8382000481, G8925327636, G9000069621, G9000219279, G9000279231, G911061179, G969889393
OpenAlex ID: W3007903124