{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:26:25Z","timestamp":1753881985384,"version":"3.41.2"},"reference-count":47,"publisher":"World Scientific Pub Co Pte Ltd","issue":"05","funder":[{"name":"YCH Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Bioinform. Comput. Biol."],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:p> The peroxisome proliferator-activated receptor-[Formula: see text] (PPAR[Formula: see text]) is a member of PPAR nuclear receptor family, and its antagonists have been widely used to treat pediatric metabolic disorders. Traditional type-1 and type-2 PPAR[Formula: see text] antagonists are all small-molecule compounds that have been developed to target the ligand-binding site (LBS) of PPAR[Formula: see text], which is not overlapped with the coactivator-interacting site (CIS) of PPAR[Formula: see text]. In this study, we described the rational design of type-3 peptidic antagonists that can directly disrupt PPAR[Formula: see text]\u2013coactivator interaction by physically competing with coactivator proteins for the CIS site. In the procedure, seven reported PPAR[Formula: see text] coactivator proteins were collected and eight 11-mer helical peptide segments that contain the core PPAR[Formula: see text]-binding LXXLL motif were identified in these coactivators, which, however, possessed a large flexibility and intrinsic disorder when splitting from coactivator protein context, and thus would incur a considerable entropy penalty (i.e. indirect readout) upon binding to PPAR[Formula: see text] CIS site. By carefully examining the natively folded conformation of these helical peptides in their parent protein context and in their interaction mode with the CIS site, we rationally designed a hydrocarbon bridge across the solvent-exposed, ([Formula: see text], [Formula: see text]+ 4) residues to constrain their helical conformation, thus largely minimizing the unfavorable indirect readout effect but having only a moderate influence on favorable enthalpy contribution (i.e. direct readout) upon PPAR[Formula: see text]\u2013peptide binding. The computational findings were further substantiated by fluorescence competition assays. <\/jats:p>","DOI":"10.1142\/s0219720022500202","type":"journal-article","created":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T03:28:35Z","timestamp":1659929315000},"source":"Crossref","is-referenced-by-count":2,"title":["Computational design and experimental confirmation of conformationally constrained peptides to compete with coactivators for pediatric PPAR\u03b1 by minimizing indirect readout effect"],"prefix":"10.1142","volume":"20","author":[{"given":"Caijie","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, Children\u2019s Hospital of Nanjing Medical University, Nanjing 210008, P.\u00a0R.\u00a0China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Emergency\/Critical Care Medicine, Children\u2019s Hospital of Nanjing Medical University, Nanjing 210008, P.\u00a0R.\u00a0China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianrong","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Emergency\/Critical Care Medicine, Children\u2019s Hospital of Nanjing Medical University, Nanjing 210008, 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