Allosteric antibody inhibition of human hepsin protease
2012 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Allosteric antibody inhibition of human hepsin protease
Koschubs, T.; Dengl, S.; Dürr, H.; Kaluza, K.; Georges, G.; Hartl, C. & Jennewein, S. et al. (2012)
Biochemical Journal, 442(2) pp. 483-494. DOI: https://doi.org/10.1042/BJ20111317
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Details
- Authors
- Koschubs, Tobias; Dengl, Stefan; Dürr, Harald; Kaluza, Klaus; Georges, Guy; Hartl, Christiane; Jennewein, Stefan; Lanzendörfer, Martin; Auer, Johannes; Stern, Alvin; Huang, Kuo-Sen; Packman, Kathryn; Gubler, Ueli; Kostrewa, Dirk; Ries, Stefan; Hansen, Silke; Kohnert, Ulrich; Cramer, Patrick ; Mundigl, Olaf
- Abstract
- Hepsin is a type II transmembrane senile 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 alpha 3-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.
- Issue Date
- 2012
- Journal
- Biochemical Journal
- ISSN
- 0264-6021
- Language
- English