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Allosteric antibody inhibition of human hepsin protease.

Abstract
Hepsin is a type II transmembrane serine protease that is expressed in several human tissues. Overexpression of hepsin has been found to correlate with tumour progression and metastasis, which is so far best studied for prostate cancer, where more than 90% of such tumours show this characteristic. To enable improved future patient treatment, we have developed a monoclonal humanized antibody that selectively inhibits human hepsin and does not inhibit other related proteases. We found that our antibody, hH35, potently inhibits hepsin enzymatic activity at nanomolar concentrations. Kinetic characterization revealed non-linear, slow, tight-binding inhibition. This correlates with the crystal structure we obtained for the human hepsin-hH35 antibody Fab fragment complex, which showed that the antibody binds hepsin around α3-helix, located far from the active centre. The unique allosteric mode of inhibition of hH35 is distinct from the recently described HGFA (hepatocyte growth factor activator) allosteric antibody inhibition. We further explain how a small change in the antibody design induces dramatic structural rearrangements in the hepsin antigen upon binding, leading to complete enzyme inactivation.
AuthorsTobias Koschubs, Stefan Dengl, Harald Dürr, Klaus Kaluza, Guy Georges, Christiane Hartl, Stefan Jennewein, Martin Lanzendörfer, Johannes Auer, Alvin Stern, Kuo-Sen Huang, Kathryn Packman, Ueli Gubler, Dirk Kostrewa, Stefan Ries, Silke Hansen, Ulrich Kohnert, Patrick Cramer, Olaf Mundigl
JournalThe Biochemical journal (Biochem J) Vol. 442 Issue 3 Pg. 483-94 (Mar 15 2012) ISSN: 1470-8728 [Electronic] England
PMID22132769 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Serine Proteinase Inhibitors
  • HGF activator
  • Serine Endopeptidases
  • hepsin
Topics
  • Allosteric Regulation
  • Animals
  • Antibodies, Monoclonal (chemistry, pharmacology)
  • Crystallography, X-Ray
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Protein Conformation
  • Serine Endopeptidases (metabolism)
  • Serine Proteinase Inhibitors (chemistry, pharmacology)
  • Transfection

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