PXD066095-1

PXD066095 is an original dataset announced via ProteomeXchange.

Title	Structure–Function Relationships and Therapeutic Potential of Non-Covalent PPARγ Inverse Agonists
Description	Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated therapeutic target for type 2 diabetes (T2D), but current FDA-approved agonists such as the glitazones are limited by adverse effects. SR10171, a non-covalent partial inverse agonist with modest binding potency, improves insulin sensitivity in mice without bone loss or marrow adiposity. Here, we characterize a series of SR10171 analogs to define structure-function relationships using biochemical assays, hydrogen-deuterium exchange (HDX), and computational modeling. Analogs featuring flipped indole scaffolds with alkyl substitutions exhibited 10-100-fold enhanced binding to PPARγ while retaining inverse agonist activity. HDX and molecular dynamic simulations revealed that ligand-induced dynamics within ligand-binding pocket and AF2 domain correlate with enhanced receptor binding. Lead analogs restored receptor activity in loss-of-function PPAR variants and improved insulin sensitivity in adipocytes from a diabetic patient. These findings provide mechanistic insights into non-covalent PPARγ modulation establishing a framework for developing safer, next-generation insulin sensitizers for metabolic disease therapy.
HostingRepository	PRIDE
AnnounceDate	2025-11-15
AnnouncementXML	Submission_2025-11-15_14:53:59.937.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kuang-Ting Kuo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-13 12:41:39	ID requested
⏵ 1	2025-11-15 14:54:00	announced

Dataset with its publication pending

submitter keyword: None

Patrick R.
contact affiliation	Professor, Molecular Medicine & Scientific Director, The Wertheim UF Scripps Institute
contact email	pgriffin2@ufl.edu
lab head
Kuang-Ting Kuo
contact affiliation	Scripps Research
contact email	ktkuo@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/2025/11/PXD066095

PRIDE project URI

• PRIDE
  1. PXD066095
     1. Label: PRIDE project
     2. Name: Structure–Function Relationships and Therapeutic Potential of Non-Covalent PPARγ Inverse Agonists