Structural Basis for PPAR? Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives.

ABSTRACT: Small-molecule agonism of peroxisome proliferator-activated receptor ? (PPAR?), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPAR? in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPAR?-selective activators with markedly different structures from those of the well-known PPAR? agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPAR? activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPAR? agonists and provide insight into the design of molecules for treating dyslipidemia.

SUBMITTER: Yoshida T 

PROVIDER: S-EPMC7203124 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature