6DGQ

Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with CAY10506

Summary for 6DGQ

• Entry DOI: 10.2210/pdb6dgq/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, N-(2-{4-[(2,4-dioxo-3,4-dihydro-2H-1lambda~4~,3-thiazol-5-yl)methyl]phenoxy}ethyl)-5-[(3R)-1,2-dithiolan-3-yl]pentanamide (3 entities in total)
• Functional Keywords: nuclear receptors, tzds, drug design, therapeutic targets, transcription, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63467.77

Authors

Shang, J.,Kojetin, D.J. (deposition date: 2018-05-17, release date: 2019-05-22, Last modification date: 2023-10-11)

Primary citation

Shang, J.,Brust, R.,Griffin, P.R.,Kamenecka, T.M.,Kojetin, D.J.
Quantitative structural assessment of graded receptor agonism.
Proc.Natl.Acad.Sci.USA, 116:22179-22188, 2019

PubMed Abstract: Ligand-receptor interactions, which are ubiquitous in physiology, are described by theoretical models of receptor pharmacology. Structural evidence for graded efficacy receptor conformations predicted by receptor theory has been limited but is critical to fully validate theoretical models. We applied quantitative structure-function approaches to characterize the effects of structurally similar and structurally diverse agonists on the conformational ensemble of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). For all ligands, agonist functional efficacy is correlated to a shift in the conformational ensemble equilibrium from a ground state toward an active state, which is detected by NMR spectroscopy but not observed in crystal structures. For the structurally similar ligands, ligand potency and affinity are also correlated to efficacy and conformation, indicating ligand residence times among related analogs may influence receptor conformation and function. Our results derived from quantitative graded activity-conformation correlations provide experimental evidence and a platform with which to extend and test theoretical models of receptor pharmacology to more accurately describe and predict ligand-dependent receptor activity.

PubMed: 31611383
DOI: 10.1073/pnas.1909016116

Experimental method

X-RAY DIFFRACTION (2.45 Å)