Receptor structure-based discovery of non-metabolite agonists for the succinate receptor GPR91.

ABSTRACT:

Objective

Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools.

Methods and results

Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed. Importantly, an empty side-pocket is identified next to the succinate binding site. All this information formed the basis for a

SUBMITTER: Trauelsen M 

PROVIDER: S-EPMC5699910 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature