<b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b>
<p dir="ltr">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 i...
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2025
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Ychwanegu Tag
Dim Tagiau, Byddwch y cyntaf i dagio'r cofnod hwn!
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| _version_ | 1849927630983266304 |
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| author | Kuang-Ting Kuo (21682520) |
| author2 | Patrick R. Griffin (16519783) |
| author2_role | author |
| author_facet | Kuang-Ting Kuo (21682520) Patrick R. Griffin (16519783) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kuang-Ting Kuo (21682520) Patrick R. Griffin (16519783) |
| dc.date.none.fl_str_mv | 2025-11-25T14:04:23Z |
| dc.identifier.none.fl_str_mv | 10.6084/m9.figshare.29538518.v3 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/_b_Structural_Proteomics_Reveals_Structure-Activity_Relationships_of_Non-Covalent_PPAR_Inverse_Agonists_b_b_for_Metabolic_Disease_Therapy_b_/29538518 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biochemistry and cell biology not elsewhere classified Structural dynamics Pparg2 HDx analysis compound screening strategy adipocyte AlphaScreen LanthaScreen Gal4-UAS 3T3-L1 adipocyte differentiation Adipogenesis Insulin sensitizer molecular & dynamics docking |
| dc.title.none.fl_str_mv | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | <p dir="ltr">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.</p> |
| eu_rights_str_mv | openAccess |
| id | Manara_50f3a2a4f7c0762654f5dccfb96f027c |
| identifier_str_mv | 10.6084/m9.figshare.29538518.v3 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/29538518 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b>Kuang-Ting Kuo (21682520)Patrick R. Griffin (16519783)Biochemistry and cell biology not elsewhere classifiedStructural dynamicsPparg2HDx analysiscompound screening strategyadipocyteAlphaScreenLanthaScreenGal4-UAS3T3-L1 adipocyte differentiationAdipogenesisInsulin sensitizermolecular & dynamics docking<p dir="ltr">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.</p>2025-11-25T14:04:23ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.6084/m9.figshare.29538518.v3https://figshare.com/articles/dataset/_b_Structural_Proteomics_Reveals_Structure-Activity_Relationships_of_Non-Covalent_PPAR_Inverse_Agonists_b_b_for_Metabolic_Disease_Therapy_b_/29538518CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/295385182025-11-25T14:04:23Z |
| spellingShingle | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> Kuang-Ting Kuo (21682520) Biochemistry and cell biology not elsewhere classified Structural dynamics Pparg2 HDx analysis compound screening strategy adipocyte AlphaScreen LanthaScreen Gal4-UAS 3T3-L1 adipocyte differentiation Adipogenesis Insulin sensitizer molecular & dynamics docking |
| status_str | publishedVersion |
| title | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| title_full | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| title_fullStr | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| title_full_unstemmed | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| title_short | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| title_sort | <b>Structural Determinants of Non-Covalent PPARγ Inverse Agonism and Their Therapeutic Implications</b> |
| topic | Biochemistry and cell biology not elsewhere classified Structural dynamics Pparg2 HDx analysis compound screening strategy adipocyte AlphaScreen LanthaScreen Gal4-UAS 3T3-L1 adipocyte differentiation Adipogenesis Insulin sensitizer molecular & dynamics docking |