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What are G protein-coupled receptors?

G protein-coupled receptors, or GPCRs, are a critical class of membrane protein responsible for transporting chemical signals from the extracellular matrix into the cell. There are hundreds of distinct GPCRs encoded by the human genome, specific to a variety of signaling molecules from ions to small proteins. Due to their ubiquitous nature, GPCRs have been associated with a wide variety of diseases and are actively being investigated as drug targets by the pharmaceutical industry.

Despite the promise of GPCRs, we only know a small fraction of their structures and most remain undruggable. This is due to the inherent difficulty of crystallizing and analyzing membrane proteins, which often necessitate complex sample preparation in order to produce crystals of appropriate size for crystallography.

Cryo-EM of GPCR structures

Cryo-electron microscopy (cryo-EM) is an increasingly popular life science technique due to its ability to generate high-resolution 3D structures for complex biological samples without the need for crystallization. This makes cryo-EM ideally suited for the analysis of membrane proteins, such as GPCRs, and there is a rapidly increasing number of cryo-EM membrane protein structures in the protein databank. Not only are these structures high-resolution, but they are often corroborated by multiple research groups, pointing to the reliability and utility of cryo-EM for this kind of analysis.

Benefits of cryo-EM analysis of GPCRs

Beyond enabling structure-based drug design for a wider range of GPCRs, cryo-EM has additional advantages that make it a promising component of the drug discovery process.

Most critically, cryo-EM provides active state structures for GPCRs, including low-affinity states. Even at low resolutions this can provide valuable insight into binding sites and can assist in modeling efforts. Research groups have successfully used cryo-EM to observe conformational rearrangements, to pinpoint drug-receptor interactions, and to investigate the specificity of Gs- and Gi-class G-proteins.

It is worth noting that all these observations were made early in the drug discovery process, enabling pharmaceutical companies to use structural insights to guide drug design.

Cryo-electron microscopes for GPCR structure analysis

Cryo-EM instrumentation has become significantly more approachable in recent years. What was once a highly specialized instrument requiring a dedicated expert operator can now be used by any researcher thanks to a bevy of ease-of-use and automation improvements.

The Thermo Scientific Glacios Cryo-TEM has reliably produced ~3.2 Å structures, whereas the higher-resolution Thermo Scientific Krios Cryo-TEM regularly generates ~2 Å resolution data. On top of that, automation improvements have reduced throughput time so that entirely novel structures can be obtained in as little as one week. This makes Thermo Scientific cryo-EM instrumentation ideally suited for the fast pace of pharmaceutical research, providing high-quality analysis for structure-based drug design.

Case study: GLP1R

Glucagon-like peptide-1 receptor (GLP1R) is a critical pharmacological target in the treatment of metabolic disorders. In fact, peptides that mimic the function of GLP-1 (e.g. semaglutide or liraglutide) are already being prescribed for the treatment of type-2 diabetes and for chronic weight management. These peptides are currently administered via injection; structural characterization of their binding sites would allow for the development of small molecule alternatives that could be administered orally.

Timeline of GLP1R GPCR structures determined with cryo-EM.
Brief timeline of published GLP1R structures determined with cryo-EM. Despite originating from multiple groups and facilities, structures of similar resolution were able to be obtained. Note that GLP1R is just one type of GPCR, and other receptor structures are also being actively investigated, with similar results.

Highlighting the accessibility of cryo-EM, multiple research groups have already used this technique to determine the structure of GLP1R at sufficient resolution to visualize not just the binding pocket but even hydrogen bonds and water molecules. These structural insights are accelerating lead optimization by showing how the molecular machinery of the peptide is impacting downstream signaling.


Techniques

Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

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MicroED

MicroED is an exciting new technique with applications in the structural determination of small molecules and protein. With this method, atomic details can be extracted from individual nanocrystals (<200 nm in size), even in a heterogeneous mixture.

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Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

Learn more ›

MicroED

MicroED is an exciting new technique with applications in the structural determination of small molecules and protein. With this method, atomic details can be extracted from individual nanocrystals (<200 nm in size), even in a heterogeneous mixture.

Learn more ›

Samples


Proteins Analysis

Cryo-electron microscopy provides near-atomic resolution 3D protein structure. It can determine structural information for complexes and crystallization-resistant samples, as well as vital cellular context.

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Biopharmaceutical Research

Structural drug discovery is enabled by cryo-electron microscopy, as the method provides near-atomic-resolution detail for small molecules and protein biologics in their fully hydrated state.

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Virus Analysis

Cryo-EM enables the 3D structural visualization of virus particles, and the antigen-antibody interface, at near-atomic resolutions. A virus’s inherent structural symmetry makes it the ideal target for cryo-EM analysis.

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Resources

Products

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Krios Rx Cryo-TEM

  • Industry leading productivity and ease of use
  • Fixed 300 kV voltage for SPA only
  • Pharma-dedicated service package for guaranteed reliability

Krios G4 Cryo-TEM

  • Improved ergonomics
  • Fits more easily into new and existing labs
  • Maximized productivity and automation
  • Best image quality for high-resolution 3D reconstruction

Glacios Cryo-TEM

  • Flexible Accelerating Voltage 80-200 kV
  • Industry-leading Autoloader for cryogenic sample manipulation
  • Small footprint
  • Enhanced ease-of-use

Tundra Cryo-TEM

  • Structural information at biologically relevant resolution
  • Space efficient and cost effective
  • Easy, iterative sample optimization
  • Unique AI algorithms for streamlined data collection

Vitrobot System

  • Fully automated sample vitrification
  • Blotting device
  • Semi-automated grid transfer
  • High sample throughput

Selectris and Selectris X Imaging Filters

  • Designed for high stability and atomic resolution imaging
  • Straightforward operation
  • Paired with the latest generation Thermo Scientific Falcon 4i Direct Electron Detector

EPU 2 Software

  • Microscope-embedded solution for single particle acquisition
  • Optimized for high-throughput particle collection
  • Compatible with film, CCD cameras, and direct electron detectors

Falcon 4i Detector

  • High throughput for more images per hour
  • Unsurpassed imaging quality with high DQE
  • Lossless data compression with EER

Ceta-D Camera

  • Optimum performance at any high tension (20–300 kV)
  • Compatible with post-column filters and spectrometers
  • Movie acquisition for dynamic studies

EM Services for Pharma

  • Maximize output with system uptime and throughput commitments
  • Drive improvement with enhanced visibility to system data
  • Comprehensive maintenance and applications support

EM Services for Single Particle Analysis

  • Empower your users so they can work with confidence
  • Keep step-by-step workflow guidance at your fingertips
  • Get set up for success with Workflow Validation

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Electron microscopy services for
the life sciences

To ensure optimal system performance, we provide you access to a world-class network of field service experts, technical support, and certified spare parts.

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