7E2O

X-ray Crystal structure of PPARgamma R288H mutant.

Summary for 7E2O

• Entry DOI: 10.2210/pdb7e2o/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma (2 entities in total)
• Functional Keywords: peroxisome proliferator-activated receptor, r288h, transcription factor, ligand binding domain, apo form, nuclear protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 62860.95

Authors

Egawa, D.,Itoh, T. (deposition date: 2021-02-06, release date: 2022-01-19, Last modification date: 2023-11-29)

Primary citation

Egawa, D.,Ogiso, T.,Nishikata, K.,Yamamoto, K.,Itoh, T.
Structural Insights into the Loss-of-Function R288H Mutant of Human PPAR gamma.
Biol.Pharm.Bull., 44:1196-1201, 2021

PubMed 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.

PubMed: 34471047
DOI: 10.1248/bpb.b21-00253

Experimental method

X-RAY DIFFRACTION (3.2 Å)