Sebastian Mathea

Native Flow-Induced Dispersion Analysis – Mass Spectrometry Enables Automated, Multiplexed Ligand Screening from Conventional, Nonvolatile Buffers Native electrospray ionization mass spectrometry has become an important method for the discovery and validation of noncovalent ligands for therapeutic targets. As a label-free method combining high sensitivity and chemical specificity, it is ideally suited for this application. However, the performance of the method is severely impacted by the presence of nonvolatile buffers and salts, and there is a risk of ion suppression if a target protein is coincubated with multiple candidate ligands. These factors, along with the fairly labor-intensive nature, required operator skill, and limited throughput of most implementations, represent significant obstacles to the widespread adoption of native mass spectrometry-based ligand discovery. Here, we demonstrate the combination of flow-induced dispersion analysis with native mass spectrometry for screening of ligands for an E3 ligase and two kinases of pharmacological relevance. Importantly, this approach avoids ion suppression and formation of salt adducts without the need for offline desalting or buffer exchange, and each multiplexed measurement of a sample consisting of a target protein and a mixture of more than 20 candidate ligands took only a few minutes. Because the method is largely automated, this screening technology represents a potentially important step toward making native mass spectrometry a mainstream biophysical technique in drug discovery.

Native Flow-Induced Dispersion Analysis – Mass Spectrometry Enables Automated, Multiplexed Ligand Screening from Conventional, Nonvolatile Buffers #AC pubs.acs.org/doi/10.1021/...

PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinsons disease https://www.biorxiv.org/content/10.1101/2025.03.19.644182v1

More than 2 decades ago the PINK1 protein was found to be linked to Parkinson's disease, but its structure and how it was activated was not known. Until @science.org today. A triumph for cryo-EM and structural biology, introducing new targets for drug intervention.
www.science.org/doi/10.1126/...

There are 16 random mutations - aim was to stabilize the recombinant kinase domain - the variant can be expressed in E. coli (in contrast to WT BRAF).

PubMed PubMed® comprises more than 37 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full text content from PubMed Central a...

Another step in the DOGE apocalypse: pubmed has gone missing (at the moment): pubmed.ncbi.nlm.nih.gov

LRRK2 type-II inhibitor design strategy.

Aberrant increases in kinase activity of LRKK2 are associated with #PD. In this study, CRN Team Reck-Peterson designed & tested the first LRRK2-selective type-II kinase inhibitors 🧪

🔗 Check out the full #preprint: www.biorxiv.org/content/10.1...

An update with latest data available for graph of life expectancy vs health care expenditures per capita for 20 countries and one outlier.

Moving the fat: Emerging roles of rab GTPases in the regulation of lipid droplet contact sites Lipid droplets (LDs) play crucial roles in lipid metabolism, energy homeostasis, and cellular stress. Throughout their lifecycle, LDs establish membra…

www.sciencedirect.com/science/arti...

Excited to share that dosing has begun in the Denali Phase 2a "BEACON" study of the investigational therapeutic BIIB122 in Parkinson's disease patients that carry a variant in LRRK2!

investors.denalitherapeutics.com/news-release...

Engineering and sculpturing a smaller easy-to-use CRBN for new drug discoveries

‘Easy to handle’ Cereblon – a new tool for drug discovery and molecular glue screening 👍

www.sciencedirect.com/science/arti...

Congrats to the Đikić lab and Merck KGaA, in collaboration with Enamine Ltd, the Nowak Lab, the Langer Lab and iBET 😀
#CRBN #TPD #PROTAC

A Proximity MAP of RAB GTPases RAB GTPases are the most abundant family of small GTPases and regulate multiple aspects of membrane trafficking events, from cargo sorting to vesicle budding, transport, docking, and fusion. To regula...

For my first post on Bluesky, here is our BioID map of RAB GTPases! It was a collective effort from many in the lab initiated by Benoît, Raphaëlle, and Dominique and followed up extensively by Véronique! I'll happily share the associated data if anyone is interested. www.biorxiv.org/content/10.1...

Durably reducing conspiracy beliefs through dialogues with AI Conspiracy theory beliefs are notoriously persistent. Influential hypotheses propose that they fulfill important psychological needs, thus resisting counterevidence. Yet previous failures in correctin...

Consoling: Chatting with AI can weaken beliefs in conspiracy narratives.

Suspicion: AI may be capable of tricking us into any belief...

www.science.org/doi/10.1126/...

Development of Ligands and Degraders Targeting MAGE-A3 Type I melanoma antigen (MAGE) family members are detected in numerous tumor types, and expression is correlated with poor prognosis, high tumor grade, and increased metastasis. Type I MAGE proteins a...

MAGE-A3 degraders from the @craigmcrews.bsky.social
lab. Nice example of how ligand discovery with DEL screening can mesh into degrader workflows.

Protein Degradation in Focus

We definitely don’t know all the ins and outs of degrading proteins as a therapeutic mode. But every year more stuff gets clearer:

Hook Peterpan GIF ALT: Hook Peterpan GIF

I’m growing tired of seeing “Hook effect” in the literature instead of “hook effect” — ffs people, it’s named after the shape of the dose-response curve, not everyone’s favorite pirate 🤦‍♂️

I spent my childhood in the GDR. I confirm this country was terrible. I remember the cognitive dissonance in school, avoiding classmates whose parents were probably Stasi informants, and mistrusting any authorities.

I guess growing up in a dictatorship still has a profound impact on my personality.

Developing biologics that modulate LRRK2 features:

# Cellular kinase activity
# Filament formation
# Overcome preferred orientation in cryo-EM

@asapresearch.bsky.social
www.jbc.org/article/S002...

New preprint available on Mechanism of human PINK1 activation at the TOM complex in a reconstituted system. Great collaboration featuring ASAP Project Manager, Sebastian Mathea and other researchers. Check it out! 🧪
www.biorxiv.org/content/10.1...