LEAPS Meets Life Sciences Conference

Session

Drug Discovery

17 May 2023, 16:00

Hotel Hermitage, La Biodola Bay, Elba Island, Italy

211. The First Ambient Temperature Structure of Large Ribosomal Subunit from Thermus Thermophilus

Bilge Tosun, Ms Cahine Kulakman (Koc University)

17/05/2023, 16:00

Poster

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...

203. Selecting Synthetic Photoswitches for Time-Resolved Serial Crystallography of the Human A2A Receptor

Hannah Glover (Paul Scherrer Institut)

17/05/2023, 16:15

Poster

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...

181. JINXED: Just in Time Crystallization for Easy Structure Determination of Biological Macromolecules

Alessandra Henkel (Center for Free-Electron Laser Science, DESY)

17/05/2023, 16:30

Poster

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 –...

259. Keynote 6: Structure-based drug discovery in biotech and pharma

Michael Hennig (leadXpro AG, Park Innovaare, 5234 Villigen, Switzerland)

17/05/2023, 16:45

Oral

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...

240. Structure analyze HIV-1 Gag-IP6 complexes using ambient-temperature X-ray crystallography and in-solution Small-angle X-ray scattering.

Nurettin Tokay

17/05/2023, 18:45

Oral

AIDS caused by infection of human immunodeficiency virus (HIV) is one of the big issues in the world. Antiretroviral therapy (ART) using multiple drugs has developed, and suppression of HIV in a body is possible. However, latent HIV reservoirs can be found in body, and HIV can hide for years inside reservoirs. This reservoir is resistant to ART and leads to viral rebound once the treatment is...

273. Photopharmacology: Where light and molecules meet crystallography

Amadeu Llebaria (MCS, Laboratory of Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain)

17/05/2023, 19:15

Oral

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...

257. Watching the release of a photopharmacological drug from its target using SLS and SwissFEL

Jörg Standfuss (Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen, Switzerland)

17/05/2023, 19:45

Oral

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...

274. Keynote 7: Four-dimensional structural analysis of membrane proteins and its application to drug discovery

So Iwata (Graduate School of Medicine, Kyoto University and RIKEN SPring-8 Center)

18/05/2023, 08:45

Oral

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...

216. Detuning of the ribosome conformational landscape promotes antibiotic resistance and collateral sensitivity

Guillermo Montoya (NNF-CPR University of Copenhagen), Dr Pablo Mesa (NNF-CPR)

18/05/2023, 09:30

Oral

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...

169. Watching protein-ligand interaction dynamics using X-ray free electron lasers

Joerg Standfuss (Paul Scherrer Institut)

Oral

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...