{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kuo KT"],"funding":["U.S. Department of Health & Human Services | NIH | National Institute on Aging","U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)"],"pagination":["890"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12830962"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["17(1)"],"pubmed_abstract":["Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated therapeutic target for type 2 diabetes (T2D), but current FDA-approved agonists 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 N-alkyl substitutions exhibited 10- to 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 and differential repression. Lead analogs restored receptor activity in loss-of-function PPARγ variants and improved insulin sensitivity in adipocytes from a diabetic patient. These findings elucidate mechanisms of non-covalent PPARγ modulation establishing a framework for developing safer, next-generation insulin sensitizers for metabolic disease therapy."],"journal":["Nature communications"],"pubmed_title":["Structural determinants of non-covalent PPARγ inverse agonism and their therapeutic implications."],"pmcid":["PMC12830962"],"funding_grant_id":["AG071332"],"pubmed_authors":["Garcia-Ordonez RD","He Y","Bruning JB","Ruiz C","Griffin PR","Chang MR","Kuo KT","McDougal DP","Kamenecka TM","Bdiri B","Cameron MD"],"additional_accession":[]},"is_claimable":false,"name":"Structural determinants of non-covalent PPARγ inverse agonism and their therapeutic implications.","description":"Peroxisome proliferator-activated receptor gamma (PPARγ) is a validated therapeutic target for type 2 diabetes (T2D), but current FDA-approved agonists 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 N-alkyl substitutions exhibited 10- to 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 and differential repression. Lead analogs restored receptor activity in loss-of-function PPARγ variants and improved insulin sensitivity in adipocytes from a diabetic patient. These findings elucidate mechanisms of non-covalent PPARγ modulation establishing a framework for developing safer, next-generation insulin sensitizers for metabolic disease therapy.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Dec","modification":"2026-06-06T22:01:19.737Z","creation":"2026-06-05T03:12:08.069Z"},"accession":"S-EPMC12830962","cross_references":{"pubmed":["41419463"],"doi":["10.1038/s41467-025-67608-5"]}}