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Structural Insights into the Loss-of-Function R288H Mutant of Human PPARγ. | LitMetric

AI Article Synopsis

  • PPARγ is a nuclear receptor involved in regulating metabolism and is targeted by certain diabetes medications; a mutation (R288H) in its ligand-binding domain may contribute to colon cancer risk.
  • The R288H mutation alters the structure of PPARγ, particularly affecting interactions between key amino acids that stabilize its configuration.
  • This structural change impairs the binding of natural ligands, providing insight into why the R288H mutation compromises PPARγ's function.

Article Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and the molecular target of thiazolidinedione-class antidiabetic drugs. It has been reported that the loss of function R288H mutation in the human PPARγ ligand-binding domain (LBD) may be associated with the onset of colon cancer. A previous in vitro study showed that this mutation dampens 15-deoxy-Δ-prostaglandin J2 (15d-PGJ2, a natural PPARγ agonist)-dependent transcriptional activation; however, it is poorly understood why the function of the R288H mutant is impaired and what role this arginine (Arg) residue plays. In this study, we found that the apo-form of R288H PPARγ mutant displays several altered conformational arrangements of the amino acid side chains in LBD: 1) the loss of a salt bridge between Arg288 and Glu295 leads to increased helix 3 movement; 2) closer proximity of Gln286 and His449 via a hydrogen bond, and closer proximity of Cys285 and Phe363 via hydrophobic interaction, stabilize the helix 3-helix 11 interaction; and 3) there is steric hindrance between Cys285/Gln286/Ser289/His449 and the flexible ligands 15d-PGJ2, 6-oxotetracosahexaenoic acid (6-oxoTHA), and 17-oxodocosahexaenoic acid (17-oxoDHA). These results suggest why Arg288 plays an important role in ligand binding and why the R288H mutation is disadvantageous for flexible ligand binding.

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Source
http://dx.doi.org/10.1248/bpb.b21-00253DOI Listing

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