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

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6FE8-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-6FE9-D
Genre: Journal Article
Alternative Title : J. Biol. Chem.

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 Creators:
Friedrich, R.1, Author              
Fuentes-Prior, P.2, Author              
Ong, E., Author
Coombs, G., Author
Hunter, M., Author
Oehler, R., Author
Pierson, D., Author
Gonzalez, R., Author
Huber, R.2, Author              
Bode, W.1, 2, 3, Author              
Madison, E. L., Author
Affiliations:
1Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              
2Huber, Robert / Structure Research, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565155              
3Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565144              

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 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.

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Language(s): eng - English
 Dates: 2002-01-18
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 35287
ISI: 000173421300075
 Degree: -

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Title: Journal of Biological Chemistry
  Alternative Title : J. Biol. Chem.
Source Genre: Journal
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Pages: - Volume / Issue: 277 (3) Sequence Number: - Start / End Page: 2160 - 2168 Identifier: ISSN: 0021-9258