[Seminar] Dr. Florian Gabriel "Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3"

Speaker: Dr. Florian Gabriel

Affiliation: Center for Structural Systems Biology (CSSB), EMBL and Bernhard Nocht Insitute for Tropical Medicine

Abstract

Thiamine (vitamin B1) functions as an essential coenzyme in cells. Humans and other mammals cannot synthesise this vitamin de novo and thus have to take it up from their diet. Eventually, every cell needs to import thiamine across its plasma membrane which is mainly mediated by two specific thiamine transporters SLC19A2 and SLC19A3. Loss of function mutations in either of these transporters lead to detrimental, life-threatening metabolic disorders. SLC19A3 is furthermore a major site of drug interactions. Many medications, including antidepressants, antibiotics and chemotherapeutics are known to inhibit this transporter, with potentially fatal consequences for patients. Despite a thorough functional characterisation over the past two decades, the structural basis of its transport mechanism and drug interactions has remained elusive. We report seven cryo-electron microscopy (cryo-EM) structures of the human thiamine transporter SLC19A3 in complex with various ligands. Conformation-specific nanobodies enabled us to capture different states of SLC19A3’s transport cycle, revealing the molecular details of thiamine recognition and transport. We identified seven novel drug interactions of SLC19A3 and determined structures of the transporter in complex with the inhibitors fedratinib, hydroxychloroquine and amprolium. These data allow us to develop an understanding of the transport mechanism and ligand recognition of SLC19A3. I will furthermore share some insights into nanobody discovery and structural biology in industry.