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We previously showed that two covalent ligands, T0070907 and GW9662\u2014extensively used as PPAR\u03b3 inhibitors to assess off-target activity\u2014weaken but do not completely block ligand binding via an allosteric mechanism associated with pharmacological inverse agonism (Shang and Kojetin, 2024). These covalent inhibitors shift the LBD toward a repressive conformation, where the activation function-2 (AF-2) helix 12 occupies the orthosteric pocket, competing with orthosteric ligand binding. Here, we provide additional support for this allosteric mechanism using two covalent inverse agonists, SR33065 and SR36708, which better stabilize the repressive LBD conformation and are more effective inhibitors of\u2014but also do not completely inhibit\u2014ligand cobinding. Furthermore, we show that ligand cobinding can occur with a previously reported PPAR\u03b3 dual-site covalent inhibitor, SR16832, which appears to weaken ligand binding through a direct mechanism independent of the allosteric mechanism. These findings underscore the complex nature of the PPAR\u03b3 LBD conformational ensemble and highlight the need to develop alternative methods for designing more effective covalent inhibitors.<\/jats:p>","DOI":"10.7554\/elife.106697","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T10:30:50Z","timestamp":1746700250000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106697","source":"Crossref","is-referenced-by-count":1,"title":["Shifting the PPAR\u03b3 conformational ensemble toward a transcriptionally repressive state improves covalent inhibitor efficacy"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3268-8923","authenticated-orcid":true,"given":"Liudmyla","family":"Arifova","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vm5rt34","id-type":"ROR","asserted-by":"publisher"}],"name":"Undergraduate Program in Biochemistry and Chemical Biology, Vanderbilt University","place":["Nashville, 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