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To address this concern, here we developed a potent \u201chit\u201d compound, VSP-51, which is a novel selective PPAR\u03b3-modulating ligand with improved therapeutic profiles <jats:italic>in vitro<\/jats:italic> compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPAR\u03b3 with improved insulin sensitivity due to its ability to bind PPAR\u03b3 with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPAR\u03b3 ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPAR\u03b3 with advantages over current TZD drugs.<\/jats:p>","DOI":"10.1038\/srep41487","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T12:00:58Z","timestamp":1485518458000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Identification of a novel selective PPAR\u03b3 ligand with a unique binding mode and improved therapeutic profile in vitro"],"prefix":"10.1038","volume":"7","author":[{"given":"Wei","family":"Yi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanguan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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