Cryo-Electron Microscopy

To accelerate your hit-to-lead campaign, we apply cryo-electron microscopy (cryo-EM) to provide you with 3D structures of your challenging drug targets in complex with your compounds of interest. Our protein science labs, which specialize in the production of all typical cryo-EM target classes, deliver high-quality fresh protein samples that can be directly used for in-house grid preparation. Regular access to high-end cryo-EM microscopes and more than 12 years of cumulative cryo-EM experience in industry complement our cryo-EM platform.

Tailored Cryo-EM Projects for Industry

We offer a range of cryo-EM solutions tailored to fit your needs, including:

  • stand-alone EM packages, such as negative-staining EM, to confirm sample quality
  • adaption of literature-described cryo-EM structure-determination methods to deliver target–ligand complex structures
  • complete gene-to-high-resolution-structure determination for new targets

If your target is potentially suited for X-ray and cryo-EM methods, we offer parallel feasibility studies to evaluate both, allowing for an experimentally driven decision on the optimal structure-determination strategy. In all cases, our EM projects are modular and milestone-based— after each phase, we discuss the results and conclusions with you and provide an expert recommendation on how to proceed.

Highest Protein Quality for Your Challenging Cryo-EM Target

Cryo-EM provides access to high-resolution 3D structures for challenging targets not typically accessible to classical X-ray crystallography. Our big-pharma-experienced protein science group supports your EM projects through:

  • expertise in the production of all typical cryo-EM target classes, including membrane protein, such as GPCRs and ion channels, protein–protein and protein–nucleic acid complexes, and antibody–antigen complexes
  • delivery of fresh protein directly from the final purification step for immediate in-house EM grid production, thanks to our teams being located under the same roof. This ensures the highest sample quality and avoids samples being subjected to detrimental longer incubation times and repeated freezing/thawing cycles
  • confirmation of ligand binding to the target—because the presence of a ligand can often only be confirmed at the later stages of data processing, we offer early biophysical verification of ligand binding to the cryo-EM protein construct in conditions similar to the cryo-EM condition

Fast EM Optimization Cycles for Efficient EM Projects

Typically, iterative cycles of protein optimization and grid screening and optimization are required to deliver high-resolution EM structures. Our EM platform gives us access to fast cycle times, including:

  • initial negative-staining EM quality check, which is fast and does not require much sample, gives us an early possibility of optimizing the sample quality
  • cryo-EM grid screening, which permits optimization of cryo-EM grid freezing conditions to obtain an ideally suited grid for data collection
  • regular access to both negative-staining and cryo-EM screening microscopes, which means that we can provide quick feedback to our protein science team and grid production to optimize the sample and the cryo-EM grid freezing conditions

Delivering High-Resolution Cryo-EM Structures

After the optimal cryo-EM freezing condition is identified, we collect high-resolution cryo-EM data at external high-end cryo-EM microscopes (i.e., Titan Krios). Data processing is performed in-house on our brand-new, ultra-fast cryo-EM GPU data processing server, featuring state-of-the-art processing software, such as RELION and cisTEM. Finally, our EM scientists validate and interpret the structure and provide you with all of the necessary information and guidance to best support your hit-to-lead campaign.

References

Botte, M., et al., Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation. bioRxiv (2020)