A5063220607- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Carbohydrate Chemistry and Synthesis
- Biochemical and Structural Characterization
- Cellular Mechanics and Interactions
- Cellular transport and secretion
- Immunotherapy and Immune Responses
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- RNA Interference and Gene Delivery
- Force Microscopy Techniques and Applications
- Viral Infectious Diseases and Gene Expression in Insects
- Endoplasmic Reticulum Stress and Disease
- Galectins and Cancer Biology
- Signaling Pathways in Disease
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- RNA Research and Splicing
- Biochemical and Molecular Research
- Genetic Neurodegenerative Diseases
- Yersinia bacterium, plague, ectoparasites research
- Proteoglycans and glycosaminoglycans research
- Protein purification and stability
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ProterixBio (United States)
2024
Max Planck Institute of Biochemistry
2017-2023
Freie Universität Berlin
2014-2019
Max Planck Institute of Colloids and Interfaces
2014-2019
Max Planck Society
2014-2017
Bielefeld University
2013
Multivalency as a key principle in nature has been successfully adopted for the design and synthesis of artificial glycoligands by attaching multiple copies monosaccharides to synthetic scaffold. Besides their potential various applied areas, e.g. antiviral drugs, vaccine development novel biosensors, such glycomimetics also allow deeper understanding fundamental aspects multivalent binding both natural ligands. However, most so far neglect purposeful arranged heterogeneity counterparts,...
Abstract The disassembly of integrin-containing focal adhesions (FAs) at mitotic entry is essential for cell rounding, retraction fibre formation, bipolar spindle positioning and chromosome segregation. mechanism that drives FA unknown. Here, we show the CDK1–cyclin B1 complex phosphorylates integrin activator kindlin, which results in recruitment cullin 9–FBXL10 ubiquitin ligase mediates kindlin ubiquitination degradation. This molecular pathway as phospho-inhibitory mutations CDK1 motif...
Integrin adhesion complexes are essential membrane-associated cellular compartments for metazoan life. The formation of initial integrin is a dynamic process involving focal proteins assembled at the cytoplasmic tails and inner leaflet plasma membrane. weak multivalent protein interactions within complex with membrane suggest that liquid-liquid phase separation could play role in nascent assembly. Here, we report solid-supported lipid membranes supplemented phosphoinositides induce minimal...
Integrin-mediated adhesion is essential for metazoan life. Integrin binding to ligand requires an activation step prior that depends on direct of talin and kindlin the β-integrin cytoplasmic tail transmission force from actomyosin via integrin–ligand bonds. However, affinity integrin tails low. It therefore still unclear how such low-affinity bonds are reinforced transmit forces up 10 40 pN. In this study, we use single-molecule spectroscopy by optical tweezers investigate mechanical...
Integrin affinity regulation, also termed integrin activation, is essential for metazoan life. Although talin and kindlin binding to the β-integrin cytoplasmic tail indispensable it unknown how they achieve this function. By combining NMR, biochemistry cell biology techniques, we found that β-tail can induce a conformational change increases decreases toward it. We discovered asymmetric regulation accompanied by direct interaction between kindlin, which promotes simultaneous of β-tails....
Mammalian C-type lectin receptors are involved in many aspects of immune cell regulation such as pathogen recognition, clearance apoptotic bodies and lymphocyte homing. Despite a great interest modulating receptor recognition carbohydrates, the number specific molecular probes is limited. To this end, we predicted druggability panel 22 using DoGSiteScorer. The computed scores most structures were low, characterizing family either challenging or even undruggable. further explore these...
Abstract DC‐SIGN is a cell‐surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis . Multiple attempts to develop inhibitors of the underlying carbohydrate–protein interactions have been undertaken in past fifteen years. Still, drug‐like ligands are sparse, which most likely due its hydrophilic, solvent‐exposed carbohydrate‐binding site. Herein, we report on parallel fragment screening against applying SPR and reporter displacement assay,...
The recognition of pathogen surface polysaccharides by glycan-binding proteins is a cornerstone innate host defense. Many members the C-type lectin receptor family serve as pattern receptors facilitating uptake, antigen processing, and immunomodulation. Despite high evolutionary pressure in host-pathogen interactions, it still widely assumed that genetic homology conveys similar specificities. Here, we investigate ligand specificities human murine forms myeloid langerin for simple complex...
Glycan-binding proteins are key components of central physiological and cellular processes such as self-/non-self-recognition, tissue homing, protein homeostasis. Herein, C-type lectins a diverse family that play important roles in the immune system, rendering them attractive drug targets. To evaluate lectin receptors target for small-molecule effectors, chemical probes required, which are, however, still lacking. overcome supposedly poor druggability to identify starting points probe...
C-type lectin receptors (CLRs) play a pivotal role in pathogen defense and immune homeostasis. Langerin, CLR predominantly expressed on Langerhans cells, represents potential target receptor for the development of anti-infectives or immunomodulatory therapies. As mammalian carbohydrate binding sites typically display high solvent exposure hydrophilicity, recognition natural monosaccharide ligands is characterized by low affinities. Consequently, glycomimetic ligand design poses challenges...
Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one the major glycosaminoglycans produced in small airway, decreased lungs cigarette smoke-exposed mice. To confirm protective effect KS disaccharide repeating unit designated L4 ([SO3--6]Galβ1-4[SO3--6]GlcNAc) was administered to two murine models: elastase-induced-emphysema...
Fragment-based drug discovery is a powerful complement to conventional high-throughput screening, especially for difficult targets. Screening low-molecular-weight fragments usually requires highly sensitive biophysical methods, because of the generally low affinity identified ligands. Here, we developed cell-based fragment screening assay (cellFy) that allows identification hits in physiologically more relevant environment, contrast isolated target screenings solution. For this,...
Incorporation of early druggability assessment in the drug discovery process provides a means to prioritize target proteins for high-throughput screening. We present chemical fragment arrays as method that is capable determining given with low protein and compound consumption, enabling rapid decision making during phases discovery.
Today, the process of selecting carbohydrate antigens as a basis for active vaccination and generation antibodies therapeutic diagnostic purposes is based on intuition combined with trial error experiments. In efforts to establish rational glycan epitope selection, we employed array screening, surface plasmon resonance, saturation transfer difference (STD)-NMR elucidate interactions between glycans representing Yersinia pestis lipopolysaccharide (LPS). A trisaccharide LPS inner core...
ABSTRACT The vitronectin receptor integrin αVβ5 can reside in two distinct adhesion structures – focal adhesions (FAs) and flat clathrin lattices (FCLs). Here, we investigate the mechanism that regulates subcellular distribution of β5 keratinocytes show has approximately 7- 5-fold higher affinity for adaptors ARH (also known as LDLRAP1) Numb, respectively, than talin 1 (TLN1); all proteins bind to membrane-proximal NPxY motif cytoplasmic domain. Using mass spectrometry, identified...
Fragment-based screening is an established route to identify low molecular weight molecules generate high affinity inhibitors in drug discovery. The affinities of these early hits from fragment screenings require highly sensitive biophysical technique. Saturation transfer difference (STD) NMR one the most popular methods owing its sensitivity for ligands. It would be beneficial if rank-ordering according their initial or counter-screen could performed - a selection criterion found...
Abstract FAN1 is an endo- and exo-nuclease involved in DNA interstrand crosslink repair. Genome-wide association studies of people with Huntington’s disease revealed a strong between the R507H mutation early onset, however underlying mechanism(s) remains unclear. has previously been implicated modulating triplet repeat expansion PCNA dependent manner. To examine role on activation, we solved cryo-EM structures PCNA–FAN1–DNA complex. Our findings reveal that R507 residue directly interacts...
Abstract Der Oberflächenrezeptor DC‐SIGN ermöglicht die Aufnahme von Krankheitserregern wie HIV, Ebolavirus oder Mycobacterium tuberculosis. Daher gab es zahlreiche Versuche, Inhibitoren gegen Bindung dieses Rezeptors an Kohlenhydratstrukturen dieser Pathogene zu entwickeln. Wegen der hydrophilen und wenig markanten Glykan‐Bindestelle kennt man nur wenige Wirkstoff‐ähnliche Liganden für DC‐SIGN. Parallele Fragment‐Screenings mit SPR‐Spektroskopie einem Reporter Displacement Assay ergänzen...
Integrins require an activation step before ligand binding and signaling that is mediated by talin kindlin to the β integrin cytosolic domain (β-tail). Conflicting reports exist about contribution of phosphorylation a conserved threonine motif in β1-tail (β1-pT788/pT789) activation. We show widely used commercially available antibodies against β1-pT788/pT789 do not detect specific signals immunoblots several human mouse cell lysates but bind bi-phosphorylated residues numerous proteins,...
Many biological processes from infection to tumor immune evasion are controlled by cell surface sialylation. To gather further insight into these processes, methods alter sialylation required. One way achieve this is inhibiting the key enzyme of sialic acid de novo biosynthesis, intracellular bifunctional UDP-N-acetylglucosamine epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we present low molecular weight inhibitors MNK activity based on picolinic derivatives. They were identified in...
Abstract Um neue Wirkstoffe zu identifizieren, wird heute zunehmend auf fragmentbasiertes Screening zurückgegriffen. Die dafür erforderliche hohe Empfindlichkeit in der frühen Phase Forschung liefern biophysikalische Methoden, darunter NMR‐Spektroskopie, Oberflächenplamonenresonanz‐Spektroskopie und Röntgenkristallographie.