5UGM
Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with Edaglitazone
Summary for 5UGM
| Entry DOI | 10.2210/pdb5ugm/pdb |
| Descriptor | Peroxisome proliferator-activated receptor gamma, (5R)-5-({4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-1-benzothiophen-7-yl}methyl)-1,3-thiazolidine-2,4-dione, 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 | 64168.75 |
| Authors | Shang, J.,Kojetin, D.J. (deposition date: 2017-01-09, release date: 2018-01-17, Last modification date: 2024-03-06) |
| Primary citation | Shang, J.,Brust, R.,Mosure, S.A.,Bass, J.,Munoz-Tello, P.,Lin, H.,Hughes, T.S.,Tang, M.,Ge, Q.,Kamekencka, T.M.,Kojetin, D.J. Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPAR gamma. Elife, 7:-, 2018 Cited by PubMed Abstract: Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a 'ligand link' to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand. PubMed: 30575522DOI: 10.7554/eLife.43320 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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