Proteomics

Dataset Information

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Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ


ABSTRACT: The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Bile

SUBMITTER: Bruce Pascal  

LAB HEAD: Patrick Griffin

PROVIDER: PXD016401 | Pride | 2020-01-13

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
F025553.csv Csv
F025553.dat Other
PPA74_PPAR_3Murea_1pcTFA_TCEP_MSMS_1.RAW Raw
PPARg_LBD_Apo_vs_T007_10_1.raw Raw
PPARg_LBD_Apo_vs_T007_10_2.raw Raw
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Publications

Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ.

Heidari Zahra Z   Chrisman Ian M IM   Nemetchek Michelle D MD   Novick Scott J SJ   Blayo Anne-Laure AL   Patton Trey T   Mendes Desiree E DE   Diaz Philippe P   Kamenecka Theodore M TM   Griffin Patrick R PR   Hughes Travis S TS  

Nature communications 20191220 1


The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 cha  ...[more]

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