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  Allosteric antibody inhibition of human hepsin protease

Koschubs, T., Dengl, S., Dürr, H., Kaluza, K., Georges, G., Hartl, C., et al. (2012). Allosteric antibody inhibition of human hepsin protease. Biochemical Journal, 442(3), 483-494. doi:10.1042/BJ20111317.

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Koschubs, T., Author
Dengl, S., Author
Dürr, H., Author
Kaluza, K., Author
Georges, G., Author
Hartl, C., Author
Jennewein, S., Author
Lanzendörfer, M., Author
Auer, J., Author
Stern, A., Author
Huang, K.‑S., Author
Packman, K., Author
Gubler, U., Author
Kostrewa, D., Author
Ries, S., Author
Hansen, S., Author
Kohnert, U., Author
Cramer, P.1, Author           
Mundigl, O., Author
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

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Free keywords: Fab fragment, human hepsin antibody, induced conformational change, prostate cancer, transmembrane serine protease, X-ray structure
 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.

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Language(s): eng - English
 Dates: 2011-12-022012-03-15
 Publication Status: Issued
 Pages: -
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 Rev. Type: Peer
 Identifiers: DOI: 10.1042/BJ20111317
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Title: Biochemical Journal
Source Genre: Journal
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Pages: - Volume / Issue: 442 (3) Sequence Number: - Start / End Page: 483 - 494 Identifier: -