Publications
2026
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Structural insights into multitargeting <em>Mycobacterium tuberculosis</em> Pkn kinases
Tuberculosis remains one of the leading major global health challenges, driven by the emergence of multidrug-resistant and extensively drug-resistant bacterial strains. Resistant strains complicate treatment, which often requires prolonged use of toxic second- and third-line drugs. Protein phosphorylation plays critical roles in Mycobacterium tuberculosis, with serine/threonine kinases PknA, PknB, and PknG being essential for survival, virulence, and persistence. In this study, we screened an... -
Janus kinase 2 activation loop as a regulator of catalysis and trans-activation
Protein kinases regulate essential cellular processes such as apoptosis, proliferation, and growth. Precise regulation of kinase activity is critical for proper signal transduction and is often mediated by activation-loop phosphorylation. Janus kinases (JAKs) employ a unique regulatory mechanism: they remain autoinhibited by their pseudokinase domains until cytokine stimulation triggers dimerization and trans-phosphorylation of two activation-loop tyrosines. Despite its relevance for JAK... -
A rare JAK2 mutation associated with adult-onset Still's disease and exacerbated vaccine-induced innate immune response
CONCLUSION: The JAK2R947Q germline variant identified in a patient with AOSD displays enhanced activation upon cytokine stimulation. Our results also suggest that the vaccine-induced innate immune transcriptome response could be used as benchmark in the functional assessment of genetic variants in key genetic pathways controlling immune response. -
Heritability and Transcriptional Impact of JAK3, STAT5A and STAT6 Variants in a Tyrolean Family
The Janus Kinase (JAK) and Signal Transducers and Activators of Transcription (STAT) pathways regulate a range of biological processes, including immune response and hematopoiesis. While a major research focus has been on somatic human mutations in disease, less is known about the heritability of germline variants and their physiological impact. This study addresses an important issue in population genetics: the context-dependent effects and incomplete penetrance of rare genetic variants in... -
Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications
Type I/II cytokine receptors mediate cytokine-specific biological responses by employing a defined combination of four Janus kinases (JAKs) and seven signal transducers and activators of transcription (STATs) for cellular signal transduction. Deregulation of the JAK-STAT pathway leads to various diseases, with JAK and STAT proteins representing attractive therapeutic targets. Fifteen JAK inhibitors are approved for several immunological and haematological diseases, offering significant benefits...
2025
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Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community
The impact of most missense variants in immune regulatory genes on steady-state immune transcriptome expression in healthy individuals in real-world conditions remains largely unexplored. Here, we investigated the transcriptional impact of 21 germline variants in JAK, TYK2, and STAT family genes identified within a healthy Austrian alpine cohort. Of the 98 participants 35 carried only one variant and 32 carried two or more variants. Allele frequencies (AF) of these germline mutations, based on... -
Coxsackie B1 virus-like particle vaccine modified to exclude a highly conserved immunoreactive region from the capsid induces potent neutralizing antibodies and protects against infection in mice
CONCLUSIONS: We demonstrated that with targeted structural modification of the CVB1-VLP capsid, immunodominant antibody responses against the conserved PALXAXETG motif can be avoided. We demonstrate that structural modification of CVB1-VLP is a viable strategy. Since the deleted epitope is known to be non-neutralizing, its deletion may help focus the immune response on more protective targets and thereby improve vaccine efficacy. The modified VLPs, particularly when adjuvanted, offer a promising... -
Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target
Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good...
2024
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Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target
Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good... -
Author Correction: AI is a viable alternative to high throughput screening: a 318-target study
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Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity
Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis... -
AI is a viable alternative to high throughput screening: a 318-target study
High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that... -
Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling
Janus kinase 2 (JAK2) mediates type I/II cytokine receptor signaling, but JAK2 is also activated by somatic mutations that cause hematological malignancies by mechanisms that are still incompletely understood. Quantitative superresolution microscopy (qSMLM) showed that erythropoietin receptor (EpoR) exists as monomers and dimerizes upon Epo stimulation or through the predominant JAK2 pseudokinase domain mutations (V617F, K539L, and R683S). Crystallographic analysis complemented by kinase...
2023
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The RNA-binding protein Snd1/Tudor-SN regulates hypoxia-responsive gene expression
Snd1 is an evolutionarily conserved RNA-binding protein implicated in several regulatory processes in gene expression including activation of transcription, mRNA splicing, and microRNA decay. Here, we have investigated the outcome of Snd1 gene deletion in the mouse. The knockout mice are viable showing no gross abnormalities apart from decreased fertility, organ and body size, and decreased number of myeloid cells concomitant with decreased expression of granule protein genes. Deletion of Snd1... -
Development of an enzyme-coupled activity assay for Janus kinase 2 inhibitor screening
JAK2 transmits signals of several important cytokines, such as growth hormone and erythropoietin. The interest toward the therapeutic targeting of JAK2 was boosted in 2005, when the somatic JAK2 V617F mutation, responsible for the majority of myeloproliferative neoplasms (MPNs) was discovered. JAK2 inhibitors have been approved for MPN therapy and they are effective in alleviating symptoms and improving the quality of life of the patients, but they do not lead to molecular remission. This calls... -
Differences in JAK Isoform Selectivity Among Different Types of JAK Inhibitors Evaluated for Rheumatic Diseases Through In Vitro Profiling
CONCLUSION: Inhibition of JAK kinase activity did not directly translate into cellular inhibition of JAK/STAT signaling. Despite differences in JAK selectivity, the cytokine inhibition profiles of currently approved Jakinibs were highly similar, with preference for JAK1-mediated cytokines. Novel types of Jakinibs showed narrow cytokine inhibition profile specific for JAK3- or TYK2-mediated signaling. -
Identification of Novel Small Molecule Ligands for JAK2 Pseudokinase Domain
Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of...