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J. Biol. Chem., Vol. 280, Issue 10, 9578-9585, March 11, 2005

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X-ray Structure of Human proMMP-1

NEW INSIGHTS INTO PROCOLLAGENASE ACTIVATION AND COLLAGEN BINDING^*

Daniela Jozic, Gleb Bourenkov, Ngee-Han Lim¶, Robert Visse¶, Hideaki Nagase¶||, Wolfram Bode, and Klaus Maskos**

From the Max-Planck-Institut für Biochemie, Abteilung Strukturforschung, Am Klopferspitz 18a, D-82152 Martinsried, Germany, ^¶Kennedy Institute of Rheumatology Division, Imperial College London, 1 Aspenlea Road, Hammersmith, London W6 8LH, United Kingdom, and AG Proteindynamik Max-Planck-Gesellschaft-Arbeitsgruppen für strakturelle Molekularbiologie c/o Deutsches Elektronen Synchrotron, D-22603 Hamburg, Germany

Vertebrate collagenases, members of the matrix metalloproteinase (MMP) family, initiate interstitial fibrillar collagen breakdown. It is essential in many biological processes, and unbalanced collagenolysis is associated with diseases such as arthritis, cancer, atherosclerosis, aneurysm, and fibrosis. These metalloproteinases are secreted from the cell as inactive precursors, procollagenases (proMMPs). To gain insights into the structural basis of their activation mechanisms and collagen binding, we have crystallized recombinant human proMMP-1 and determined its structure to 2.2 Å resolution. The catalytic metalloproteinase domain and the C-terminal hemopexin (Hpx) domain show the classical MMP-fold, but the structure has revealed new features in surface loops and domain interaction. The prodomain is formed by a three-helix bundle and gives insight into the stepwise activation mechanism of proMMP-1. The prodomain interacts with the Hpx domain, which affects the position of the Hpx domain relative to the catalytic domain. This interaction results in a "closed" configuration of proMMP-1 in contrast to the "open" configuration observed previously for the structure of active MMP-1. This is the first evidence of mobility of the Hpx domain in relation to the catalytic domain, providing an important clue toward the understanding of the collagenase-collagen interaction and subsequent collagenolysis.

Received for publication, September 27, 2004

The atomic coordinates and structure factors (code 1SU3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Fonds der Chemischen Industrie, the European Union projects cancerdegradome LSH-2002-2.2 "combating cancer" and QLK3-CT-2002-02136 "profiling MMP inhibition," the European Commission as SPINE, contract no. QLG2-CT-2002-00988 under the Integrated programme "Quality of Life and Management of Living Resources," Wellcome Trust Grant 057508, and National Institutes of Health Grant AR 39189. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence may be addressed. Tel.: 44208-83834488; Fax: 44208-83834994; E-mail: h.nagase{at}imperial.ac.uk. ^** To whom correspondence may be addressed. Tel.: 4989-85782827; Fax: 4989-85783516; E-mail: maskos{at}biochem.mpg.de.

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