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Related Experiment Video

Updated: Nov 6, 2025

Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization

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Published on: March 16, 2020

Evolving cryo-EM structural approaches for GPCR drug discovery.

Xin Zhang¹, Rachel M Johnson¹, Ieva Drulyte²

¹Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia.

Structure (London, England : 1993)

|May 6, 2021

Summary

Cryo-electron microscopy (cryo-EM) now enables GPCR drug discovery without Nb35 stabilization. Lower voltage (200 kV) cryo-EM provides high-resolution structures, making it more commercially viable.

Keywords:

GPCR cryo-EM drug discovery method development patent free

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Last Updated: Nov 6, 2025

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Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy

Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy

Published on: January 7, 2019

Area of Science:

Structural biology
Biochemistry
Pharmacology

Background:

G protein-coupled receptors (GPCRs) are crucial cell surface drug targets.
Cryo-electron microscopy (cryo-EM) and complex stabilization techniques advance structure-assisted drug design for GPCR agonists.
Current limitations include nanobody 35 (Nb35) use and high-cost 300 kV imaging, hindering broad cryo-EM application in drug discovery.

Purpose of the Study:

To validate stable GPCR:Gs protein complex formation without Nb35.
To compare cryo-EM data acquisition at 200 kV versus 300 kV using different detectors.
To demonstrate the commercial viability of cryo-EM for GPCR drug discovery.

Main Methods:

Stabilization of glucagon-like peptide-1 receptor (GLP-1R) complexes with a modified Gs protein without Nb35.
Cryo-electron microscopy (cryo-EM) imaging at 200 kV and 300 kV.
Comparison of Falcon 4 and K3 direct electron detectors for image acquisition.

Main Results:

Stable GLP-1R:modified Gs protein complexes were formed without Nb35.
A 3.2 Å resolution cryo-EM map was achieved using a 200 kV Glacios-Falcon 4 system.
The map showed clear density for the bound drug PF 06882961 and ordered water molecules.

Conclusions:

Cryo-EM can be applied to GPCR drug discovery without Nb35.
Lower voltage (200 kV) cryo-EM with appropriate detectors yields high-resolution structural data.
This approach enhances the commercial applicability of cryo-EM for GPCR-targeted drug discovery.