6MD2

Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with GW9662 and Arachidonic acid

Summary for 6MD2

• Entry DOI: 10.2210/pdb6md2/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-chloro-5-nitro-N-phenylbenzamide, ARACHIDONIC ACID, ... (4 entities in total)
• Functional Keywords: nuclear receptors, tzds, drug design, therapeutic targets, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64061.32

Authors

Shang, J.,Kojetin, D.J. (deposition date: 2018-09-03, release date: 2019-01-09, Last modification date: 2024-10-09)

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

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: 30575522
DOI: 10.7554/eLife.43320

Experimental method

X-RAY DIFFRACTION (2.2 Å)