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Karsten Niefind   Professor  Senior Scientist or Principal Investigator 
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Karsten Niefind published an article in July 2018.
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Top co-authors See all
Werner Hummel

74 shared publications

Faculty of Chemistry; Bielefeld University; Universitätsstr. 25 33615 Bielefeld Germany

Andrew D. Abell

56 shared publications

ARC Center of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced SensingThe University of Adelaide Australia

Josef Altenbuchner

42 shared publications

Institute for Industrial Genetics, University of Stuttgart, 70569 Stuttgart, Germany

Ulrich Baumann

24 shared publications

Department für Chemie, Institut für Biochemie, Universität zu Köln, Otto-Fischer-Str. 12-14, D-50674 Köln, Germany

Jane E Parker

23 shared publications

Max-Planck Institute for Plant Breeding Research

80
Publications
28
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6
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386
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Publication Record
Distribution of Articles published per year 
(1997 - 2018)
Total number of journals
published in
 
21
 
Publications See all
Article 2 Reads 0 Citations Crystal structure of highly glycosylated human leukocyte elastase in complex with an S2′ site binding inhibitor Jennifer Hochscherf, Markus Pietsch, William Tieu, Kevin Kua... Published: 26 July 2018
Acta Crystallographica Section F Structural Biology Communications, doi: 10.1107/s2053230x1800537x
DOI See at publisher website
PREPRINT-CONTENT 3 Reads 0 Citations An EDS1 EP-domain surface mediating timely transcriptional reprogramming of immunity genes Deepak Dharamchand Bhandari, Dmitry Lapin, Barbara Kracher, ... Published: 05 July 2018
Plant Biology, doi: 10.1101/362921
DOI See at publisher website ABS Show/hide abstract
Plant intracellular NLR receptors recognize pathogen interference to trigger immunity. NLR signalling mechanisms have not been resolved. Enhanced disease susceptibility1 (EDS1) heterodimers are recruited by Toll-interleukin1-receptor domain NLRs (TNLs) to transcriptionally mobilize resistance pathways. Using an Arabidopsis EDS1 heterodimer crystal structure we interrogate the conserved but functionally uncharacterized EDS1 α-helical EP-domain. We identify EP-domain positively charged residues lining a cavity that are essential for TNL immunity signalling, beyond heterodimer formation. Mutating arginine (R493) to alanine creates a weak EDS1 allele which disables TNL immunity against bacteria producing a virulence factor, coronatine (COR). Arabidopsis plants expressing EDS1R493A are slow to mobilize defence gene expression changes, independently of COR. The transcriptional delay has severe consequences for pathogen resistance and for countering bacterial COR. We uncover a set of host immunity genes whose repression by COR is blocked by wild-type EDS1 but not by EDS1R493A in the TNL response. These data uncover an EDS1 signalling surface lining the heterodimer EP-domain cavity which confers timely transcriptional reprogramming of host defence pathways and blocks bacterial virulence in NLR receptor immunity.
Article 0 Reads 0 Citations Improved protein-crystal identification by using 2,2,2-trichloroethanol as a fluorescence enhancer Christian Pichlo, Christine Toelzer, Konrad Chojnacki, Sinan... Published: 24 April 2018
Acta Crystallographica Section F Structural Biology Communications, doi: 10.1107/s2053230x18005253
DOI See at publisher website
Article 4 Reads 0 Citations A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Bindin... Alexander Schnitzler, Andreas Gratz, Andre Bollacke, Michael... Published: 17 February 2018
Pharmaceuticals, doi: 10.3390/ph11010023
DOI See at publisher website ABS Show/hide abstract
Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[b,d]furan-3(2H)-one (4a) and (E)-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[b,d]furan-2,7-diol (5) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM (4a) and 5 nM (5) and an apparent Ki value of 0.4 nM for both. Compounds 4a and 5 reduced cellular CK2 activity, indicating cell permeability. Cell viability was substantially impaired in LNCaP cells, as well as apoptosis was induced, which was not appearing in non-neoplastic ARPE-19 cells. Co-crystallization of 4a and 5 revealed an unexpected π-halogen bond of the chloro substituent at C9 with the gatekeeper amino acid Phe113, leading to an inverted binding mode in comparison to parent compound 4b, with the Cl at C6 instead, which was co-crystallized as a control. This indicates that the position of the chloro substituent on ring A of the dibenzofuran scaffold is responsible for an inversion of the binding mode that enhances potency.
Article 0 Reads 0 Citations Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structu... Jennifer Hochscherf, Dirk Lindenblatt, Benedict Witulski, Ro... Published: 13 December 2017
Pharmaceuticals, doi: 10.3390/ph10040098
DOI See at publisher website PubMed View at PubMed ABS Show/hide abstract
Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2α and CK2α′, the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2α/CK2α′, but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydro-gen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2α structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix αD region conformation and of the salt content in the crystallization medium.
Article 0 Reads 1 Citation A novel esterase subfamily with α/β-hydrolase fold suggested by structures of two bacterial enzymes homologous tol-homos... Christine Tölzer, Sonia Pal, Hildegard Watzlawick, Josef Alt... Published: 28 December 2015
FEBS Letters, doi: 10.1002/1873-3468.12031
DOI See at publisher website PubMed View at PubMed
Conference papers
CONFERENCE-ARTICLE 18 Reads 0 Citations Unusual binding modes of two inhibitors to their target enzymes human leukocyte elastase (HLE) and protein kinase CK2 re... Jennifer Hochscherf, Karsten Niefind Published: 31 October 2018
doi: 10.3390/ecmc-4-05572
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The main subjects of this keynote are protein kinase CK2 and human leukocyte elastase (HLE), two biomedically important enzymes and pharmacologically attractive targets.

CK2 - more precisely its catalytic subunit CK2alpha - is a member of the superfamily of eukaryotic protein kinases. Its antiapoptotic activity is exploited by tumour cells in order to escape cell death. The indeno[1,2-b]indole scaffold, a flat annulated 4-ring system, is a relatively novel lead structure for the development of ATP-competitive CK2 inhibitors. Complex structures of CK2alpha and a number of indeno[1,2-b]indole-type compounds had been predicted previously. In such an in silico model the inhibitor sticks in the ATP cavity in an apparently plausible way, namely such that its hydrophobic side is directed inwards while its hydrophilic side has access to the solvent. However, when we determined the first co-crystal of CK2alpha with an indeno[1,2-b]indole-type inhibitor, we realized to our surprise that the orientation of the inhibitor was reversed: the "hydrophobic-out/oxygen-out" binding mode that we discovered is determined by hydrogen bonds of the inhibitor to a hidden and conserved water molecule. This molecular arrangement requires an inhibitor orientation in which hydrophobic substitutents are at the outer surface which opens the possibility for further modifications.

The second target enzyme, human leukocyte elastase (HLE), is a chymotrypsin-type serine protease which is produced by neutrophilic granulocytes, the most abundant cells of the innate immune system [therefore the synonym "human neutrophil elastase" (HNE)]. The activity of HLE must be strictly controlled to avoid proteolytic damage of the connective tissue which is a particular problem in chronic obstructive pulmonary disease (COPD) and other inflammatory diseases. Naturally, HLE is downregulated by alpha1-antitrypsin, a serpin-type protease inhibitor, which is likewise produced by neutrophils. Synthetic HLE inhibitors are useful in cases of inbalance of the natural HLE control system. Typically, HLE inhibibitors block the S1 pocket of the enzyme, the most critical of several substrate binding cavities. The S1 pocket recognizes the side chain of the substrate directly N-terminal of the peptide bond to be hydrolyzed. In our study we co-crystallized HLE with a 1,3-thiazolidine-2,4-dione derivative with antibacterial activity that had been observed to inhibit HLE as well. In the complex structure the inhibitor is bound to the S2' site, i.e. at a region responsible for harbouring residues at the C-terminal side of the scissile peptide bond. In addition, the inhibitor seems to induce a dimerization of the enzyme by which the access to the active site region is prohibited.

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