6PDZ

Crystal structure of PPARgamma ligand binding domain in complex with SMRT peptide and inverse agonist T0070907

Summary for 6PDZ

• Entry DOI: 10.2210/pdb6pdz/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, Nuclear receptor corepressor 2, 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide, ... (4 entities in total)
• Functional Keywords: nuclear receptors, tzds, drug design, therapeutic targets, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 68654.36

Authors

Shang, J.,Kojetin, D.J. (deposition date: 2019-06-19, release date: 2020-03-04, Last modification date: 2024-10-09)

Primary citation

Shang, J.,Mosure, S.A.,Zheng, J.,Brust, R.,Bass, J.,Nichols, A.,Solt, L.A.,Griffin, P.R.,Kojetin, D.J.
A molecular switch regulating transcriptional repression and activation of PPAR gamma.
Nat Commun, 11:956-956, 2020

PubMed 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.

PubMed: 32075969
DOI: 10.1038/s41467-020-14750-x

Experimental method

X-RAY DIFFRACTION (2.1 Å)