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Jennifer Hochscherf     Other 
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Jennifer Hochscherf published an article in July 2018.
Top co-authors
Karsten Niefind

79 shared publications

Department of Chemistry, Institute of Biochemistry, Universität zu Köln, Zülpicher Str. 47, 50674 Cologne, 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

Markus Pietsch

16 shared publications

Institute II of Pharmacology, Center of Pharmacology, Medical Faculty; University of Cologne; Gleueler Strasse 24 50931 Cologne Germany

Publication Record
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published in
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
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
DOI See at publisher website ABS Show/hide abstract

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.