PXD016401

PXD016401 is an original dataset announced via ProteomeXchange.

Title	Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-01-13
AnnouncementXML	Submission_2020-01-13_05:53:13.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bruce Pascal
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-22 01:58:18	ID requested
⏵ 1	2020-01-13 05:53:15	announced

Heidari Z, Chrisman IM, Nemetchek MD, Novick SJ, Blayo AL, Patton T, Mendes DE, Diaz P, Kamenecka TM, Griffin PR, Hughes TS, . Nat Commun, 10(1):5825(2019) [pubmed]

submitter keyword: nuclear receptor, PPARγ, protein structure

Patrick Griffin
contact affiliation	Scripps Florida
contact email	pgriffin@scripps.edu
lab head
Bruce Pascal
contact affiliation	Scripps Florida
contact email	bpascal@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/01/PXD016401

PRIDE project URI

• PRIDE
  1. PXD016401
     1. Label: PRIDE project
     2. Name: Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ