Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode.

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 PPAR? 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 PPAR? and PPAR?, respectively. In PPAR? 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 PPAR? provides a rationale for the different activation of the ligand towards PPAR? and PPAR?, suggesting a novel basis for ligand design.

SUBMITTER: Capelli D 

PROVIDER: S-EPMC5052532 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature