 |
PDBsum entry 6dgo
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription/transcription inhibitor
|
PDB id
|
|
|
|
6dgo
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Quantitative structural assessment of graded receptor agonism.
|
|
|
Authors
|
|
J.Shang,
R.Brust,
P.R.Griffin,
T.M.Kamenecka,
D.J.Kojetin.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2019,
116,
22179-22188.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
