A5018683664- PARP inhibition in cancer therapy
- Biochemical and Molecular Research
- Amino Acid Enzymes and Metabolism
- Enzyme Structure and Function
- Toxin Mechanisms and Immunotoxins
- Metabolism and Genetic Disorders
- DNA Repair Mechanisms
- RNA Research and Splicing
- Folate and B Vitamins Research
- RNA modifications and cancer
- Enzyme Production and Characterization
- Calcium signaling and nucleotide metabolism
- Porphyrin Metabolism and Disorders
- 14-3-3 protein interactions
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Chronic Lymphocytic Leukemia Research
- Peptidase Inhibition and Analysis
- Endoplasmic Reticulum Stress and Disease
- Integrated Circuits and Semiconductor Failure Analysis
- ATP Synthase and ATPases Research
- Electrostatic Discharge in Electronics
- Heat shock proteins research
- Biochemical Acid Research Studies
Karolinska Institutet
2010-2021
Lund University
2002-2010
International Institute of Molecular and Cell Biology
2009
Stockholm University
2009
CRUK/MRC Oxford Institute for Radiation Oncology
2009
Genomics (United Kingdom)
2009
Université Claude Bernard Lyon 1
2007
Centre National de la Recherche Scientifique
2007
Université Paris Cité
2002
Institute of Biochemistry and Biophysics, Polish Academy of Sciences
2002
Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 PARP and commonly used research tools for their multiple enzymes. also determined crystal structures these compounds bound to PARP1 or PARP2. Veliparib niraparib are selective PARP2; olaparib, rucaparib, talazoparib more potent but less selective. PJ34 UPF1069 broad inhibitors; inserts a flexible moiety into hydrophobic...
Besides thriving on altered glucose metabolism, cancer cells undergo glutaminolysis to meet their energy demands. As the first enzyme in catalyzing glutaminolysis, human kidney-type glutaminase isoform (KGA) is becoming an attractive target for small molecules such as BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide], although regulatory mechanism of KGA remains unknown. On basis crystal structures, we reveal that binds allosteric pocket at dimer interface KGA,...
The PARP-3 protein is closely related to the PARP-1 and PARP-2 proteins, which are involved in DNA repair genome maintenance. Here, we characterized biochemical properties of human PARP-3. able ADP-ribosylate itself as well histone H1, a previously unknown substrate for not activated upon binding mono-ADP-ribosylase, contrast PARP-2. interacts with activates absence DNA, resulting synthesis polymers ADP-ribose. N-terminal WGR domain this activation. functional interaction between suggests...
The 70-kDa heat shock proteins (Hsp70) are chaperones with central roles in processes that involve polypeptide remodeling events. Hsp70 consist of two major functional domains: an N-terminal nucleotide binding domain (NBD) ATPase activity, and a C-terminal substrate (SBD). We present the first crystal structures four human isoforms, those NBDs HSPA1L, HSPA2, HSPA5 HSPA6. As previously family members, all crystallized closed cleft conformation, although slight opening through rotation...
DEXD/H-box RNA helicases couple ATP hydrolysis to remodeling by an unknown mechanism. We used x-ray crystallography and biochemical analysis of the human protein DDX19 investigate its regulatory The crystal structures DDX19, in RNA-bound prehydrolysis free posthydrolysis state, reveal α-helix that inserts between conserved domains negatively regulate ATPase activity. This finding was corroborated data confirm autoregulatory function N-terminal region protein. is first study describing a open...
Abstract Despite the immense importance of enzyme–substrate reactions, there is a lack general and unbiased tools for identifying prioritizing substrate proteins that are modified by enzyme on structural level. Here we describe high-throughput proteomics method called System-wide Identification prioritization Enzyme Substrates Thermal Analysis (SIESTA). The approach assumes enzymatic post-translational modification likely to change their thermal stability. In our proof-of-concept studies,...
We report two crystal structures of the PARP domain human tankyrase-2 (TNKS2). Tankyrases are involved in fundamental cellular processes such as telomere homeostasis and Wnt signaling. The complex TNKS2 with potent inhibitor XAV939 provides insights into molecular basis strong interaction suggests routes for further development tankyrase inhibitors.
DEAD-box RNA helicases play various, often critical, roles in all processes where RNAs are involved. Members of this family proteins linked to human disease, including cancer and viral infections. contain two conserved domains that both contribute ATP binding. Despite recent advances the molecular details how these enzymes convert chemical energy into remodeling is unknown. We present crystal structures isolated DEAD-domains DDX2A/eIF4A1, DDX2B/eIF4A2, DDX5, DDX10/DBP4, DDX18/myc-regulated...
Poly(ADP-ribose) polymerases (PARPs) activate DNA repair mechanisms upon stress- and cytotoxin-induced damage, inhibition of PARP activity is a lead in cancer drug therapy. We present structural functional analysis the domain human PARP-3 complex with several inhibitors. Of these, KU0058948 strongest inhibitor activity. The presented crystal structures highlight key features for potent binding suggest routes creating isoenzyme-specific
Abstract Protein ADP-ribosylation is a reversible post-translational modification that regulates important cellular functions. The identification of modified proteins has proven challenging and mainly been achieved via enrichment methodologies. Random mutagenesis was used here to develop an engineered Af1521 ADP-ribose binding macro domain protein with 1000-fold increased affinity towards ADP-ribose. crystal structure reveals two point mutations K35E Y145R form salt bridge within the domain....
Poly-ADP-ribose polymerases (PARPs) catalyze transfer of ADP-ribose from NAD(+) to specific residues in their substrate proteins or growing chains. PARP activity is involved processes such as chromatin remodeling, transcription control, and DNA repair. Inhibitors may be useful cancer therapy. PARP2 the family member that most similar PARP1, two can act together heterodimers. We used X-ray crystallography determine structures catalytic domain human PARP2: complexes with inhibitors...
Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most cellular targets are poorly characterized. Here, we describe an inhibitor ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), regulator DNA repair mitotic progression. In vitro profiling against 12 members enzyme family suggests selectivity ARTD3, crystal structures illustrate molecular basis selectivity. The compound active in...
Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been target for cancer drug development decades. Current PARP inhibitors are generally non-selective, inhibit mono-ADP-ribosyltransferases...
Abstract Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in phosphopeptide groove, an amphipathic C-terminal helix ExoS ExoT has been thought to crucial for their activation. However, crystal structures 14-3-3β:ExoS -ExoT complexes presented here reveal extensive hydrophobic interface is sufficient complex formation toxin We show C-terminally...