The study presents the first observation of critical steps in protein synthesis at temperatures close to those in the human body using ultrafast and ultrabright X-ray free electron laser (XFEL) pulses. Over half of known antibiotics target prokaryotic ribosomes, the site of protein synthesis, and the large ribosomal subunit (50S) is specifically targeted by antibiotics such as macrolides and...
Time-resolved serial crystallography has emerged as a method to study protein dynamics at atomic resolution. In this method, reactions need to be initiated synchronously. Many experiments have used light as a trigger system to study endogenously photoactive proteins; however, only a small fraction of proteins are naturally photoactive. Therefore, work needs to be done to ensure this method can...
Macromolecular crystallography is a well-established method in structural biology and after focusing on static structures, the method is now developing towards the investigation of structural dynamics, e.g. by looking at protein-ligand or enzyme-substrate interactions. In time-resolved serial crystallography and room-temperature data collection, the reaction is triggered within the crystals –...
Advances in structure determination and computational methods facilitate the discovery and optimization of pharmaceutical active compounds in the majority of all projects. Still, integral membrane proteins are drug targets for more than 60% of all approved drugs, but are underexplored because of their challenges to be expressed, purified and get high resolution structures or enable biophysical...
Azobenzene photoisomerization can be chemically implemented in protein ligands to actuate on biological receptors and to manipulate their activity with light. Azobenzene small molecule photoswitches can be designed and synthesized to serve for real-time regulation of receptors with high spatiotemporal accuracy using specific illumination patterns. The basis for this is a different interaction...
Photopharmacology offers a powerful approach to alter ligand affinity and biological activity of small molecule drugs using light as a trigger. However, understanding the molecular mechanisms underlying this process has been challenging due to the inability of conventional structural biology to resolve the relevant transitions. In this presentation, I will outline how we employed time-resolved...
We are studying drug discovery targeting membrane proteins. In particular, GPCRs are our main targets, and we are investigating the complex structures of receptors and compounds to elucidate action mechanisms of these compounds and lead to novel drug discovery.
In the first part of my talk, we will discuss the X-ray structure of the complex of orexin 2 receptor and a dual orexin receptor...
Around 50% of the current antibiotic arsenal targets the ribosome, thus resistance to ribosome-targeting antibiotics poses severe challenges to antimicrobial treatments. Here, we characterize a 12-nucleotide deletion in the rplF gene encoding the uL6 ribosomal protein, which was identified in a tobramycin-resistant strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. To...
The molecular structure of protein-ligand complexes provides much insight into the biochemical processes in living cells. However, to understand protein activation, we also need to resolve how proteins interact with their many small molecule ligands over time. In this presentation, I will outline the opportunities and challenges of using X-ray free electron lasers to follow protein-ligand...
