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Science 4 June 1999:
Vol. 284. no. 5420, pp. 1667 - 1670
DOI: 10.1126/science.284.5420.1667
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Reports

Structure of Human Pro-Matrix Metalloproteinase-2: Activation Mechanism Revealed

Ekaterina Morgunova, 12 Ari Tuuttila, 1 Ulrich Bergmann, 1 Mikhail Isupov, 3 Ylva Lindqvist, 2 Gunter Schneider, 2* Karl Tryggvason 1*

Matrix metalloproteinases (MMPs) catalyze extracellular matrix degradation. Control of their activity is a promising target for therapy of diseases characterized by abnormal connective tissue turnover. MMPs are expressed as latent proenzymes that are activated by proteolytic cleavage that triggers a conformational change in the propeptide (cysteine switch). The structure of proMMP-2 reveals how the propeptide shields the catalytic cleft and that the cysteine switch may operate through cleavage of loops essential for propeptide stability.

1 Division of Matrix Biology, Department of Medical Biochemistry and Biophysics and
2 Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
3 Schools of Chemistry and Biological Sciences, University of Exeter, UK.
*   To whom correspondence should be addressed. E-mail: gunter{at}alfa.mbb.ki.se (G.S.); karl.tryggvason{at}mbb.ki.se (K.T.).

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E. I. Chen, S. J. Kridel, E. W. Howard, W. Li, A. Godzik, and J. W. Smith (2002)
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W. R. English, B. Holtz, G. Vogt, V. Knauper, and G. Murphy (2001)
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V. Quaranta (2000)
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L. L. Johnson, A. G. Pavlovsky, A. R. Johnson, J. A. Janowicz, C.-F. Man, D. F. Ortwine, C. F. Purchase II, A. D. White, and D. J. Hupe (2000)
J. Biol. Chem. 275, 11026-11033
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The Molecular Perspective: Matrix Metalloproteinase 2.
D. S. Goodsell (1999)
Oncologist 4, 509-511
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TIMP-2 Is Required for Efficient Activation of proMMP-2 in Vivo.
Z. Wang, R. Juttermann, and P. D. Soloway (2000)
J. Biol. Chem. 275, 26411-26415
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Identification of Structural Elements Important for Matrix Metalloproteinase Type V Collagenolytic Activity as Revealed by Chimeric Enzymes. ROLE OF FIBRONECTIN-LIKE DOMAIN AND ACTIVE SITE OF GELATINASE B.
T. J. O'Farrell and T. Pourmotabbed (2000)
J. Biol. Chem. 275, 27964-27972
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Identification of the 183RWTNNFREY191 Region as a Critical Segment of Matrix Metalloproteinase 1 for the Expression of Collagenolytic Activity.
L. Chung, K.-i. Shimokawa, D. Dinakarpandian, F. Grams, G. B. Fields, and H. Nagase (2000)
J. Biol. Chem. 275, 29610-29617
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Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils.
O. Kleifeld, P. E. Van den Steen, A. Frenkel, F. Cheng, H. L. Jiang, G. Opdenakker, and I. Sagi (2000)
J. Biol. Chem. 275, 34335-34343
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The Isolation, Characterization, and Molecular Cloning of a 75-kDa Gelatinase B-like Enzyme, a Member of the Matrix Metalloproteinase (MMP) Family. AN AVIAN ENZYME THAT IS MMP-9-LIKE IN ITS CELL EXPRESSION PATTERN BUT DIVERGES FROM MAMMALIAN GELATINASE B IN SEQUENCE AND BIOCHEMICAL PROPERTIES.
E. A. Hahn-Dantona, R. T. Aimes, and J. P. Quigley (2000)
J. Biol. Chem. 275, 40827-40838
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The 1.8-A Crystal Structure of a Matrix Metalloproteinase 8-Barbiturate Inhibitor Complex Reveals a Previously Unobserved Mechanism for Collagenase Substrate Recognition.
H. Brandstetter, F. Grams, D. Glitz, A. Lang, R. Huber, W. Bode, H.-W. Krell, and R. A. Engh (2001)
J. Biol. Chem. 276, 17405-17412
   Abstract »    Full Text »    PDF »
X-ray Absorption Studies of Human Matrix Metalloproteinase-2 (MMP-2) Bound to a Highly Selective Mechanism-based Inhibitor. COMPARISON WITH THE LATENT AND ACTIVE FORMS OF THE ENZYME.
O. Kleifeld, L. P. Kotra, D. C. Gervasi, S. Brown, M. M. Bernardo, R. Fridman, S. Mobashery, and I. Sagi (2001)
J. Biol. Chem. 276, 17125-17131
   Abstract »    Full Text »    PDF »
Involvement of Fibronectin Type II Repeats in the Efficient Inhibition of Gelatinases A and B by Long-chain Unsaturated Fatty Acids.
A. Berton, V. Rigot, E. Huet, M. Decarme, Y. Eeckhout, L. Patthy, G. Godeau, W. Hornebeck, G. Bellon, and H. Emonard (2001)
J. Biol. Chem. 276, 20458-20465
   Abstract »    Full Text »    PDF »
Substrate Hydrolysis by Matrix Metalloproteinase-9*.
S. J. Kridel, E. Chen, L. P. Kotra, E. W. Howard, S. Mobashery, and J. W. Smith (2001)
J. Biol. Chem. 276, 20572-20578
   Abstract »    Full Text »    PDF »
Gelatin-binding Region of Human Matrix Metalloproteinase-2. SOLUTION STRUCTURE, DYNAMICS, AND FUNCTION OF THE COL-23 TWO-DOMAIN CONSTRUCT.
K. Briknarova, M. Gehrmann, L. Banyai, H. Tordai, L. Patthy, and M. Llinas (2001)
J. Biol. Chem. 276, 27613-27621
   Abstract »    Full Text »    PDF »


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