Coupling of receptor conformation and ligand orientation determine graded activity
Open Access
- 10 October 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 6 (11), 837-843
- https://doi.org/10.1038/nchembio.451
Abstract
The ability of constrained mutants of the estrogen receptor ligand-binding domain to dictate different conformations of bound partial agonists indicates that the ability of compounds to stabilize each state determines the degree of agonist activity. Small molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.Keywords
This publication has 49 references indexed in Scilit:
- NFκB selectivity of estrogen receptor ligands revealed by comparative crystallographic analysesNature Chemical Biology, 2008
- A solution NMR study showing that active site ligands and nucleotides directly perturb the allosteric equilibrium in aspartate transcarbamoylaseProceedings of the National Academy of Sciences, 2007
- Structural plasticity in the oestrogen receptor ligand‐binding domainEMBO Reports, 2007
- Dynamically driven protein allosteryNature Structural & Molecular Biology, 2006
- Visualizing polynucleotide polymerase machines at workThe EMBO Journal, 2006
- Intrinsic dynamics of an enzyme underlies catalysisNature, 2005
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- Structural Analysis of Autoinhibition in the Ras Activator Son of SevenlessCell, 2004
- Structural Evidence for Feedback Activation by Ras·GTP of the Ras-Specific Nucleotide Exchange Factor SOSCell, 2003
- Structural characterization of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonismNature Structural & Molecular Biology, 2002