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  Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10

Debela, M., Magdolen, V., Bode, W., Brandstetter, H., & Goettig, P. (2016). Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10. Biological Chemistry, 397(12), 1251-1264.

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[] Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10.pdf (Publisher version), 3MB
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[] Structural basis for the Zn2+ inhibition of the zymogen-like kallikrein-related peptidase 10.pdf
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©2016, Peter Goettig et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
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 Creators:
Debela, Mekdes1, Author              
Magdolen, Viktor2, Author
Bode, Wolfram3, Author              
Brandstetter, Hans2, Author
Goettig, Peter2, Author
Affiliations:
1Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565145              
2external, ou_persistent22              
3Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              

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Free keywords: SINGLE NUCLEOTIDE POLYMORPHISMS; PROSTATE-SPECIFIC ANTIGEN; HUMAN TISSUE KALLIKREIN; RAY CRYSTAL-STRUCTURE; SERINE-PROTEASE; BREAST-CANCER; CONFORMATIONAL SELECTION; ACTIVATION PROFILES; BIOLOGICAL-FLUIDS; TUMOR-SUPPRESSORBiochemistry & Molecular Biology; activation domain; anomalous signal; kallikrein loop; structural disorder; zinc inhibition;
 Abstract: Although kallikrein-related peptidase 10 (KLK10) is expressed in a variety of human tissues and body fluids, knowledge of its physiological functions is fragmentary. Similarly, the pathophysiology of KLK10 in cancer is not well understood. In some cancer types, a role as tumor suppressor has been suggested, while in others elevated expression is associated with poor patient prognosis. Active human KLK10 exhibits a unique, three residue longer N-terminus with respect to other serine proteases and an extended 99-loop nearly as long as in tissue kallikrein KLK1. Crystal structures of recombinant ligand-free KLK10 and a Zn2+ bound form explain to some extent the mixed trypsin-and chymotrypsin-like substrate specificity. Zn2+-inhibition of KLK10 appears to be based on a unique mechanism, which involves direct binding and blocking of the catalytic triad. Since the disordered N-terminus and several loops adopt a zymogen-like conformation, the active protease conformation is very likely induced by interaction with the substrate, in particular at the S1 subsite and at the unusual Ser193 as part of the oxyanion hole. The KLK10 structures indicate that the N-terminus, the nearby 75-, 148-, and the 99-loops are connected in an allosteric network, which is present in other trypsin-like serine proteases with several variations.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000387888700006
DOI: 10.1515/hsz-2016-0205
 Degree: -

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Title: 6th International Symposium on Kallikreins and Kallikrein-Related Peptidases (ISK)
Place of Event: Brisbane, AUSTRALIA
Start-/End Date: 2015-09-28 - 2015-10-01

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Title: Biological Chemistry
  Other : Biological Chemistry Hoppe-Seyler (Berlin)
  Abbreviation : Biol Chem Hoppe Seyler
Source Genre: Journal
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Publ. Info: Berlin : W. de Gruyter
Pages: - Volume / Issue: 397 (12) Sequence Number: - Start / End Page: 1251 - 1264 Identifier: Other: 1437-4315
ISSN: 1431-6730
CoNE: https://pure.mpg.de/cone/journals/resource/954927622123