The TBSGC continues to enhance its structural biology capabilities by integrating advanced instruments for cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET). This expansion allows the study of macromolecular complexes unsuitable for crystallography and facilitates the resolution of drug targets within their native environment, such as Mtb cells. Recent developments in single-particle cryo-EM have enabled atomic-level structure determination of large complexes, while cryo-ET and subtomogram averaging now offer the ability to examine ribosome structures at atomic resolution within bacterial cells treated with different antibiotics. This innovative approach provides a unique opportunity to investigate in-situ structures of potential Mtb drug targets synergistically.
The Texas A&M core lab has established a cutting-edge cryo-EM center featuring a Titan Krios cryo-electron microscope equipped with advanced technology, including a Volta phase plate and a Biocontinuum energy-filtered K3 camera. Directed by Dr. Junjie Zhang, the center provides state-of-the-art instrumentation for specimen preparation and high-resolution cryo-EM/ET data collection, enhancing the TBSGC’s structural biology capabilities.
Target selection stems from synergy screens using chemi-genomic interactions to identify potential drug targets. Ribosomes, essential for protein synthesis, expand investigations to key machineries in protein homeostasis, such as ClpXP protease and RNA degradosome, known Mtb drug targets. Examining ribosomes, membrane transporters , and complexes like MurA-CwlM inside cells provides insights into synergy among enzymes, especially with newly developed drugs. The approach enhances understanding and potential drug discovery for Mtb, particularly focusing on essential cellular processes like cell wall biosynthesis.
Image - Journal Cover showing our Mtb ribosome structure.
Image - Our new Titan Krios G4 cryo-electron microscope that is available to the TBSGC.
Our fundamental aims for this program are :