| 1. |
- Karlberg, Tobias, et al.
(författare)
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14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.
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| 2. |
- Andersson, C David, et al.
(författare)
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Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:17, s. 7706-7718
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Tidskriftsartikel (refereegranskat)abstract
- The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.
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| 3. |
- Ekblad, Torun, et al.
(författare)
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Towards small molecule inhibitors of mono-ADP-ribosyltransferases
- 2015
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 95, s. 546-551
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Tidskriftsartikel (refereegranskat)abstract
- Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is 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 a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.
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| 4. |
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| 5. |
- Lindgren, Anders E. G., et al.
(författare)
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Chemical Probes to Study ADP-Ribosylation : Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:23, s. 9556-9568
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Tidskriftsartikel (refereegranskat)abstract
- The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
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| 6. |
- Lindgren, Anders E. G., et al.
(författare)
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PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 8:8, s. 1698-1703
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Tidskriftsartikel (refereegranskat)abstract
- Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.
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| 7. |
- Röijezon, Ulrik, 1970-
(författare)
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Sensorimotor function in chronic neck pain : objective assessments and a novel method for neck coordination exercise
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic neck pain is a widespread problem that causes individual suffering as well as large costs for the society. The knowledge about the pathophysiology is poor and therefore specific diagnosis and causal treatment are rare. Important knowledge for characterization of the disorders has been gained from research on sensorimotor functions in people with neck pain. Moreover, rehabilitation regimes including sensorimotor exercises indicate promising results.The main objectives of this thesis were to extend the knowledge on sensorimotor dysfunctions in chronic neck pain, and to develop a new exercise method for improving sensorimotor functions of the neck. The studies focused on aspects of postural control and movements of the arm and neck. These are vital functions for many activities of daily living. People with chronic (>3 months) neck pain were compared to healthy controls (CON). Neck pain related to trauma was referred to as whiplash associated disorders (WAD), while neck pain without association to trauma was referred to as non-specific (NS).Arm-functioning was assessed in a pointing task. WAD and NS had reduced pointing precision compared to CON. The reduced precision was associated with self-rated difficulties performing neck movements, physical functioning, and in WAD, also pain and balance disturbances.Postural control was assessed in quiet standing on a force platform without vision. The center of pressure signal was decomposed into it’s slow and fast components. WAD and NS were compared to CON. The results revealed an effect of age on the magnitude of the fast sway component, but no effect of group. The magnitude of the slow component was elevated in both WAD and NS. This increase was associated with self-rated balance disturbance, arm-functioning, difficulties to run and sensory alterations in WAD, while in NS, the increase in the slow sway component was associated with concurrent low back pain.Neck movements were assessed in a cervical axial rotation test with maximal speed. In total 8 variables representing basic kinematics, including variables reflecting movement smoothness and conjunct motions were calculated. NS were compared to CON. Linear discriminant modelling indicated Peak Speed and conjunct motions as significant classification variables that together had a sensitivity of 76.3% and specificity of 77.6%. Retest reliability was good for Peak Speed but poor for the measure of conjunct motions. Peak Speed was slower in NS compared to CON, and even slower in a sub-group of NS with concurrent low back pain. Reduced Peak Speed was associated with self-rated difficulties performing neck movements, car driving, running, sleeping disturbances and pain.The clinical applicability of a novel method for neck coordination exercise was assessed in a pilot study on persons with NS. The results supported the applicability and indicated positive effects of the exercise: reduced postural sway in quiet standing and increased smoothness in cervical rotations. Indications on improvement in self-rated disability and fear of movement were seen at six months follow up.In conclusion, sensorimotor functions can be altered in chronic neck pain, particularly in neck disorders with concurrent low back pain and WAD. The discriminative ability and clinical validity displayed in pointing precision, postural sway and cervical axial rotation speed imply that such tests can be valuable tools in the assessment of chronic neck pain patients, and for selecting and evaluating treatment interventions. Indications of improvements seen in the pilot-study support a future RCT.
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