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

Abstract

The type II 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 A and bovine pancreatic trypsin inhibitor at 2.9 A. 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.

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@article{Friedrich2002CatalyticDS, title={Catalytic domain structures of MT-SP1/matriptase, a matrix-degrading transmembrane serine proteinase.}, author={Rainer W. Friedrich and Pablo Fuentes-Prior and Edgar Ong and Gary Coombs and Michael J. Hunter and Ryan Oehler and Diane Pierson and Richard D. Gonzalez and Robert Huber and Wolfram Bode and Edwin L. Madison}, journal={The Journal of biological chemistry}, year={2002}, volume={277 3}, pages={2160-8} }