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Catalytic domain structures of MT-SP1/matriptase, a matrix- degrading transmembrane serine proteinase

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons77975

Friedrich,  R.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77982

Fuentes-Prior,  P.
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78142

Huber,  R.
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77772

Bode,  W.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;
Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society;
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Friedrich, R., Fuentes-Prior, P., Ong, E., Coombs, G., Hunter, M., Oehler, R., et al. (2002). Catalytic domain structures of MT-SP1/matriptase, a matrix- degrading transmembrane serine proteinase. Journal of Biological Chemistry, 277(3), 2160-2168.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-6FE8-F
Abstract
The type 11 transmembrane multidomain serine proteinase MT- SP1/matriptase is highly expressed in many human cancer-derived cell lines and has been implicated in extracellular matrix re- modeling, tumor growth, and metastasis. We have expressed the catalytic domain of MT-SP1 and solved the crystal structures of complexes with benzamidine at 1.3 Angstrom and bovine pancreatic trypsin inhibitor at 2.9 Angstrom. MT-SP1 exhibits a trypsin-like serine proteinase fold, featuring a unique nine- residue 60-insertion loop that influences interactions with protein substrates. The structure discloses a trypsin-like S1 pocket, a small hydrophobic S2 subsite, and an open negatively charged S4 cavity that favors the binding of basic P3/P4 residues. A complementary charge pattern on the surface opposite the active site cleft suggests a distinct docking of the preceding low density lipoprotein receptor class A domain. The benzamidine crystals possess a freely accessible active site and are hence well suited for soaking small molecules, facilitating the improvement of inhibitors. The crystal structure of the MT-SP1 complex with bovine pancreatic trypsin inhibitor serves as a model for hepatocyte growth factor activator inhibitor 1, the physiological inhibitor of MT-SP1, and suggests determinants for the substrate specificity.