Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases.
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Mac Sweeney, Aengus, Gil Parrado, Shirley, Vinzenz, Daniela, Bernardi, Anna, Hein, Andreas, Bodendorf, Ursula, Erbel, Paulus, Logel, Claude and Gerhartz, Bernd (2008) Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases. Journal of Molecular Biology, 384 (1). pp. 228-239. ISSN 1089-8638
Abstract
Procollagen C-peptidase, also known as bone morphogenetic protein 1 (BMP-1), is a multidomain, zinc endopeptidase of the astacin M12A family. BMP-1 is the prototype of a small group of proteases that have key roles in extracellular matrix formation and morphogenesis. BMP-1, its splice form mTLD, and the related proteases TLL-1 and TLL-2 are considered as promising drug targets for the treatment of excessive fibrosis and muscle wasting. We report here the crystal structures of the protease domains of human BMP-1 and the closely related Tolloid-like protease 1 (TLL-1). The crystal structures reveal an unexpected conformation of a cysteine-rich loop within the active site, and suggest that a flap movement is required in order to allow substrate binding. On the basis of these substantial differences between the BMP-1 and astacin active sites, a structural basis for their differing substrate specificities is proposed.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | astacin; vicinal disulfide; fibrosis |
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| Date Deposited: | 14 Dec 2009 13:49 |
| Last Modified: | 31 Jan 2013 00:59 |
| URI: | https://oak.novartis.com/id/eprint/1082 |