A new way to inhibit pyroptosis! Anja characterized by biochemical means six nanobodies that were raised against human Gasdermin D. All of them bind to the N-terminal domain of this membrane rupturing protein, but three specifically block the assembly of the membrane pore. She succeeded in crystallizing full length Gasdermin D together with two nanobodies and determined the structure at 1.9 Å resolution, providing first structural insights into the mode of action of nanobody-based Gasdermin D inhibition. Read the full story here.

 

SR-4835, a small molecule inhibitor currently in phase I clinical trials, targets transcriptional kinases Cdk12 and Cdk13. Biochemical and structural analyses could highlight SR-4835’s selectivity towards Cdk12/Cdk13 over other CMGC kinase family members. We determined the crystal structure of the Cdk12/CycK heterodimer in complex with SR-4835 at 2.7Å resolution, revealing a unique hydrogen bond network mediated by the kinase hinge region. The structural insights provided offer a foundation for optimization and design of reversible Cdk12-specific inhibitors and could facilitate the basis for the development of novel cancer therapeutics. The full study from Max and coworkers is now published in The Journal of Biological Chemistry.

Inga and Matthias wrote a review article on the “Structural aspects of inflammasome-forming NOD-like receptors” for the book Fundamentals of Inflammasome Biology, edited by Pablo Pelegrín. In this review, they provide a state-of-the-art overview of the NLR family of proteins, from conserved sequence motifs to the quaternary assembly of the inflammasome; involving NLRP or NLRC sensory proteins, the adaptor ASC, and pro-caspases as downstream effectors. They discuss whether all NLRs function according to a similar mechanism and whether targeted inhibition appears feasible for the specific treatment of inflammatory diseases. Read this review here.

We are very pleased to announce that Matthias has been awarded an ERC Advanced Grant for his proposal on the NLRP3 inflammasome. The EU will fund the work programme "Exploring inflammasome activation and targeted inhibition" (or "NalpACT" for short) for the next five years. Watch out, what comes out of this endeavour.

Niels and Gregor fishing crystals.

Our study on the type III CRISPR associated CalpL-T-S cascade has just been published in Nature. It’s an amazing story that started out of pure curiosity, when Christophe and Gregor decided to look into the structure and function of the enigmatic CalpL protease. The project really took off, when Niels joined the team and determined the crystal structure of CalpL alone and in complex with its activator cA4. Using bioinformatics, we figured out that the target of the protease is a small protein that we named CalpT. In a fantastic cooperation with the labs of Dmitri Svergun, Malcolm White, Bela Bode and Jonathan Schmid-Burgk we unraveled how the activation of CalpL works and that its target, CalpT, is an anti sigma factor that inhibits the third protein from the operon, the sigma factor CalpS. In the end, the CalpL-T-S cascade provides a direct connection between type III CRISPR mediated foreign RNA detection and the transcription machinery of the cell.

  1. New paper in Communications Biology
  2. New paper in JBC
  3. New paper in Nature Communications
  4. New paper in Nature Communications