5HZC

Crystal structure of the complex PPARgamma/AL26-29

Summary for 5HZC

• Entry DOI: 10.2210/pdb5hzc/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-methyl-2-[4-(naphthalen-1-yl)phenoxy]propanoic acid (3 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, diabetes, bundle of alpha-helices, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 66000.36

Authors

Pochetti, G.,Montanari, R.,Capelli, D.,Loiodice, F.,Laghezza, A.,Lavecchia, A. (deposition date: 2016-02-02, release date: 2016-11-23, Last modification date: 2024-01-10)

Primary citation

Capelli, D.,Cerchia, C.,Montanari, R.,Loiodice, F.,Tortorella, P.,Laghezza, A.,Cervoni, L.,Pochetti, G.,Lavecchia, A.
Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode.
Sci Rep, 6:34792-34792, 2016

PubMed Abstract: The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

PubMed: 27708429
DOI: 10.1038/srep34792

Experimental method

X-RAY DIFFRACTION (2 Å)