3T2N

Human hepsin protease in complex with the Fab fragment of an inhibitory antibody

Summary for 3T2N

• Entry DOI: 10.2210/pdb3t2n/pdb
• Related: 1O5E 1P57 1Z8G
• Descriptor: Serine protease hepsin, Antibody, Fab fragment, Heavy Chain, Antibody, Fab fragment, Light Chain, ... (4 entities in total)
• Functional Keywords: type ii transmembrane serine protease, srcr domain, substrates include pro-hepsin, pro-hgf, laminin-332, transmembrane, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type II membrane protein: P05981
• Total number of polymer chains: 6
• Total formula weight: 174682.21

Authors

Koschubs, T.,Dengl, S.,Duerr, H.,Kaluza, K.,Georges, G.,Hartl, C.,Jennewein, S.,Lanzendoerfer, M.,Auer, J.,Stern, A.,Huang, K.-S.,Kostrewa, D.,Ries, S.,Hansen, S.,Kohnert, U.,Cramer, P.,Mundigl, O. (deposition date: 2011-07-22, release date: 2011-12-28, Last modification date: 2024-11-06)

Primary citation

Koschubs, T.,Dengl, S.,Durr, H.,Kaluza, K.,Georges, G.,Hartl, C.,Jennewein, S.,Lanzendorfer, M.,Auer, J.,Stern, A.,Huang, K.S.,Packman, K.,Gubler, U.,Kostrewa, D.,Ries, S.,Hansen, S.,Kohnert, U.,Cramer, P.,Mundigl, O.
Allosteric antibody inhibition of human hepsin protease.
Biochem.J., 442:483-494, 2012

PubMed 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.

PubMed: 22132769
DOI: 10.1042/BJ20111317

Experimental method

X-RAY DIFFRACTION (2.55 Å)