Visualising a membrane receptor complex to enhance drug development

Authors: Christopher G. Tate (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Diamond Annual Review Highlight

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 17434

Abstract: A third of all FDA approved drugs target G protein-coupled receptors (GPCRs) but often have side effects. GPCRs have two signalling pathways - the G protein-coupled pathway and the arrestin-mediated pathway - and one may be the therapeutic pathway whilst the other may produce side effects. To understand this phenomenon at the molecular level, researchers needed to determine the structure of a GPCR coupled to arrestin and compare its structure to the G protein-coupled state, with the same agonist bound to both receptors. The GPCR-arrestin complex is highly mobile, which means it would not form crystals suitable for X-ray diffraction experiments. Therefore, the team used cryogenic-electron microscopy (cryo-EM) at the Electron Bio-Imaging Centre (eBIC) at Diamond Light Source to determine its structure at a 3.3Å resolution. Producing a stable GPCR-arrestin complex suitable for structure determination was still a challenge. Arrestin coupling to a GPCR requires the presence of membrane lipids, so they prepared the receptor in lipid nanodiscs. The receptor also has to be phosphorylated, so they developed a method for ligating phosphorylated peptides to the end of the receptor. Their results allowed them to identify two regions of the GPCR that could be used in the development of ‘biased’ agonists that signal predominantly through either the G protein or arrestin pathways. The structures will be an invaluable input into structure-based drug design, a powerful tool for the development of new therapeutic drugs.

Journal Keywords: Cryo-EM; GPCR; Membrane protein; Structure; Arrestin

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Other Facilities: ESRF

Added On: 12/11/2021 11:40

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)