A molecular switch regulating transcriptional repression and activation of PPARγ

Shang, Jinsai; Mosure, Sarah A.; Zheng, Jie; Brust, Richard; Bass, Jared; Nichols, Ashley; Solt, Laura A.; Griffin, Patrick R.; Kojetin, Douglas J.

doi:10.1038/s41467-020-14750-x

A molecular switch regulating transcriptional repression and activation of PPARγ

Journal Article · Tue Feb 18 23:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-14750-x· OSTI ID:1629706

^[1]; Mosure, Sarah A. ^[2]; Zheng, Jie ^[3]; Brust, Richard ^[4]; Bass, Jared ^[4]; Nichols, Ashley ^[5]; Solt, Laura A. ^[6]; ^[7]; ^[7]

Scripps Research Inst., Jupiter, FL (United States). Dept. of Integrative Structural and Computational Biology; DOE/OSTI
Scripps Research Inst., Jupiter, FL (United States). Dept. of Integrative Structural and Computational Biology; Scripps Research Inst., Jupiter, FL (United States). Skaggs graduate School of Chemical and Biological Sciences; Scripps Research Inst., Jupiter, FL (United States). Dept. of Immunology and Microbiology
Scripps Research Inst., Jupiter, FL (United States). Dept. of Integrative Structural and Computational Biology; Chinese Academy of Sciences (CAS), Shanghai (China). Shanghai Inst. of Materia Medica
Scripps Research Inst., Jupiter, FL (United States). Dept. of Integrative Structural and Computational Biology
Scripps Research Inst., Jupiter, FL (United States). Summer Undergraduate Research Fellows (SURF) program
Scripps Research Inst., Jupiter, FL (United States). Dept. of Immunology and Microbiology; Scripps Research Inst., Jupiter, FL (United States). Dept. of Molecular Medicine
Scripps Research Inst., Jupiter, FL (United States). Dept. of Integrative Structural and Computational Biology; Scripps Research Inst., Jupiter, FL (United States). Dept. of Molecular Medicine

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1629706

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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