6C1I
Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with T0070907
Summary for 6C1I
| Entry DOI | 10.2210/pdb6c1i/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide, nonanoic acid, ... (4 entities in total) |
| Functional Keywords | nuclear receptors, tzds, drug design, therapeutic targets, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 63558.61 |
| Authors | Shang, J.,Fuhrmann, J.,Brust, R.,Kojetin, D.J. (deposition date: 2018-01-04, release date: 2018-12-12, Last modification date: 2024-10-23) |
| Primary citation | Brust, R.,Shang, J.,Fuhrmann, J.,Mosure, S.A.,Bass, J.,Cano, A.,Heidari, Z.,Chrisman, I.M.,Nemetchek, M.D.,Blayo, A.L.,Griffin, P.R.,Kamenecka, T.M.,Hughes, T.S.,Kojetin, D.J. A structural mechanism for directing corepressor-selective inverse agonism of PPAR gamma. Nat Commun, 9:4687-4687, 2018 Cited by PubMed Abstract: Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor (PPAR) gamma converts a transcriptionally neutral antagonist (GW9662) into a repressive inverse agonist (T0070907) relative to basal cellular activity. X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for corepressor-selective inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide routes for developing corepressor-selective repressive PPARγ ligands. PubMed: 30409975DOI: 10.1038/s41467-018-07133-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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