High resolution 3D structures of proteins or protein-complexes
Cryo-EM has become a standard structural technique for structural determination of proteins and protein-complexes, especially for samples that limit the use for X-ray crystallography and NMR due to size, crystallization difficulty, stability, complexity and conformational variability. High resolution 3D structures of proteins and protein-complexes provide scientist with deeper understanding of biological processes, mechanisms of action of molecules, and structure-activity relationships, which can enlighten all steps of drug discovery.
3D structures of small molecules in drug discovery
3D structure determination and characterization of small molecule using cryo-EM can assist optimization of chemical synthesis, understanding of structure-activity relationship. It can also guide the design of formulation and drug delivery approach. Use of microcrystal electron diffraction (micro-ED) on small molecules serves as a better solution when NMR can only provide unclear result or X-ray crystallography is time consuming or not feasible.
Structural characterization of antibodies and their interactions with antigens
Cryo-EM is an effective technique to map the interactions between antibodies and antigens and has many applications in antibody development and biologics discovery. Structural data can be used for paratopes/epitopes identification, correlation between structures and activity, identification of cross-specificity, monoclonal antibody (MAB) optimization and IP protection. High-resolution structures showing interaction between antibodies and antigen can also be applied to guide vaccine development as an alternative to the traditional approach.
Structural characterization of lipid nanoparticles, liposomes, AAV and other viral vectors
By providing high-resolution structural information, cryo-EM can support development and manufacturing programs for the design of new drug delivery systems by characterizing shape, size and size distribution, morphology of different samples such as nanoparticles, , liposomes, Adeno Associated-Virus (AAV) and other viral like particles. These techniques has been acknowledged as a standard quality control approach in many manufacturing scenarios.
Structural biology application in PROTAC
Proteolysis targeting chimera (PROTAC) technique has drawn great attention due to its potential to target “undruggable ”proteins by linking two small-molecule binding ligands. Structural information of binding mechanism of small molecule and targeted protein or E3 ligase can significantly improve the understanding of PROTAC technique. By using cryo-EM, it is possible to visualize such binding interaction and provide insight for molecule design and searching new binding sites on targeted protein.