We had recently discovered a new signalling cascade in type III CRISPR immune systems, the CalpLTS cascade. In a nutshell, the CalpL protease senses cyclic oligonucleotides that are produced by the type III recognition complex, cleaves the anti-sigma factor CalpT and thereby releases the sigma factor CalpS. In our new study we have discovered that the multi functional CalpL protein also has a ring...

A serial switch for kinase activation: Double-phosphorylated Cdk7 turns on full activity! The Cyclin-dependent kinase 7 has two functions, it activates other CDKs to turn on the cell cycle and it phosphorylates RNA polymerase II to initiate transcription. Robert discovered that the first function does not require Cdk7 phosphorylation whereas the second function is fully boosted by the sequential p...

Congratulations to Jan Gerhartz for his first publication of a PhD in the Nowak Lab! Jan wrote a perspective article summarizing a new concept of bifunctional small molecules that can dimerize proteins and therefore generate a more potent and selective inhibitors. Small molecule inhibition relies on maintaining high occupancy of the protein target and are frequently limited for potency and selecti...

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 reso...

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 n...

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....

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...

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 activ...

The binding and hydrolysis of ATP in NLRP3 remains a conundrum: The protein requires ATP for activation, but is not simply activated by excess of nucleotide; how nucleotide exchange is regulated remains unclear, as is the correlation of ATP hydrolysis to protein activity. Rebecca, David and co-workers now analysed the nucleotide-binding Walker A and Walker B motifs, sensors 1 and 2, Glu-switch and...

Up to 50% of the population carry a single nucleotide polymorphism (SNP) in the gene encoding the inflammasome sensor Nlrp1. This SNP causes an amino acid exchange from methionine 1184 to valine (M1184V), and has been associated with several autoimmune syndromes. In collaboration with the Masters lab (The Walter and Eliza Hall Institute, Melbourne) we provide a molecular basis for the effects of t...

There it is, the long awaited structure of a TRAP transporter. Our cryo EM structure of the sialic acid transporter HiSiaPQM finally reveals the function of the enigmatic Q-domain and how the membrane domains of TRAPs are structurally and conformationally coupled to their soluble substrate binding protein. This is the result of an eight years journey and a fantastic collaboration with Gavin Thomas...

Following the movement of a protein is often extremely important to understand its function. Membrane transporters, for example, undergo a series of complicated movements to translocate a substrate. Two techniques that are often used to study such movements are PELDOR/DEER and smFRET. Both techniques can measure distances on the nanometer scale. In collaboration with the laboratory of Thorben Cord...

First steps towards structural insights into the active NLRP3 inflammasome have been taken: We have determined the directionality of ASC PYD filament growth on NLRP3 PYD nucleation seeds! In a tedious titration experiment, Inga succeeded in elongating ASC-mCherry filaments on preformed NLRP3 PYD seeds. Surprisingly, they grow on only one side for the existing filament. We determined the NLRP3 PYD ...

The long-awaited structure of full-length, human NLRP3 is here! Inga and colleagues have done a great job determining the cryo-EM structure of this inflammasomal protein in the inactive state bound to the inhibitor CRID3. In solution, the protein forms a decamer composed as pentamer of dimers. We identify a binding site that ties together five subdomains to keep the protein locked in the inactive ...

Robert – who is now in the Fisher lab at MSSM, New York – published a great paper on Cdk10/Cyclin Q in Open Biology. Cyclin-dependent kinases (CDKs) perform multiple tasks in cells, e.g., coordination of cell division or gene regulation by phosphorylating proteins. Inhibition of these kinases shows promising effects in various cancers, raising hope for improved therapies. Robert generated highly p...

Abemaciclib is a third generation CDK-directed drug used in the treatment of HR + /HER2 negative advanced or metastatic breast cancer. In a new study by Ines and co-workers, we demonstrate that members of the Homeodomain-interacting protein kinases (HIPKs) and DYRK1A are also targeted by abemaciclib. The therapeutic success of abemaciclib may therefore benefit from the simultaneous inhibition of t...

In a recent paper published in JACI, our Postdoc Jonas together with collaborators from Melbourne investigated a common variant of the inflammasome-forming NLRP1 protein, identifying functional consequences and links to asthma. Findings from this study may have implications for the treatment of asthmatic individuals carrying this variant of the NLRP1 sensor.The project was kicked off as a successf...

Robert, Ines, Max and Matthias just published a paper on the di-alcohol 1,6-hexanediol, showing that this organic chemical impairs the enzymatic activity of transcription kinases. This has a great impact on the interpretation of phosphorylation reactions in intrinsically disordered regions, as hexanediol is widely used to dissolve liquid-liquid phase separated condensates....

Martin, Niels, Janin and Gregor just published a paper about how the binding of substrates triggers the open-closed transition of the P-domain of the sialic acid TRAP transporter HiSiaQM. This was a collaboration with the laboratory of Thorben Cordes at the LMU and Gavin Thomas at the University of York....

Our paper "Crystal structure of the human NLRP9 pyrin domain suggests a distinct mode of inflammasome assembly" has just been published in FEBS Letters. We made the cover page and there is a Commentary Article by Eva de Alba....

We have just moved to our new labs and offices on the 1st floor of the BMZ building....

Our paper about the conformation of the Yersinia type-III-effector YopO in solution has just been published in Structure. Our combination of X-ray crystallography, SAXS and PELDOR distance measurements reveals large conformational changes between the apo- and actin-bound state of YopO.   ...

Our institute won a 500K grant for a new Biacore 8K machine to study protein-protein interactions. This is the first Biacore 8K in an academic lab in Germany.    ...