NPP Seminar - Dr Johannes Broichhagen, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)

Please join us for our next NPP Seminar by Dr Johannes Broichhagen from Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin and their talk, Chemical Biology Approaches to lighten up Cell Surface Proteins.

Host: Alice Adriaenssens, UCL NPP

Johannes’ research bridges organic synthesis and systems biology to provide a unique interdisciplinary approach aimed at understanding basic physiology, localization and signalling mechanisms of cell surface proteins involved in endocrine and neural disorders. He has worked extensively with Joshua Levitz to create photoswitchable ligands to characterise the role of metabotropic glutamate receptors in vivo, and has recently designed novel chemical biology tools for examining BACE1 and GLP-1R localisation and signalling at the single-molecule level.  

Abstract: 

Labelling, visualization, and functional manipulation of biomolecules is at the forefront of chemical biology.[1,2] However, selective and quantitative interrogation and analysis of biomolecules remains a challenge in the field. To tackle these issues, we employ approaches from photopharmacology, molecular biology and fluorophore design to enable biomolecule labelling and control in specific sites while elevating dye properties to the next level. To allow outstanding image quality, we designed and synthesized custom-tailored fluorophore substrates to advance photophysical and chemical properties to discern protein pools, such as the plasma membrane-bound and intracellular populations.[3] In a similar vein, we pursue unconventional strategies to design and synthesize fluorophores for super-resolution imaging in live cells. In one of our latest study, we installed carbon-deuterium bonds in fluorophores.[4] This simple modification yields dyes with increased fluorescent lifetimes, higher photostability, and enhanced brightness, improving nanoscopy and single molecule tracking. With this in hand, we focus on cell surface proteins, such as beta-secretase (BACE1) and the glucagon-like peptide 1 receptor (GLP1R). While the former is an important protease involved in the progression of Alzheimer’s disease, the latter is a class B GPCR that is involved in glucose homeostasis and satiety and a blockbuster target to treat patients suffering from type 2 diabetes. As such, it becomes incredibly important to unravel their fine interplay with custom-designed chemical biology probes. We highlight GLP1R in its endogenous context with fluorescently labelled antagonist – the LUXendins – that target the orthosteric site, allowing super resolution imaging, 2-photon imaging, single particle tracking and intravital microscopy in vivo.[5] With an expanded color palette, we enabled the use of NIR light for imaging.[6] We next genetically engineered an enzyme self-label onto GLP1R to interrogate its localization and behavior in its native context on the endogenous level.[7] This allows the tracking of GLP1R in the complex tissue setting versus different type of drugs. Taken together, we aim to use chemistry as a flashlight to shine a spotlight on the invisible in biological systems.