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.
MeSH terms
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Amino Acid Sequence
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Animals
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Astacoidea / enzymology
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Binding Sites
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Bone Morphogenetic Protein 1
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Bone Morphogenetic Proteins / antagonists & inhibitors
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Bone Morphogenetic Proteins / chemistry*
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Bone Morphogenetic Proteins / metabolism*
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Crystallography, X-Ray
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Enzyme Inhibitors / pharmacology
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Humans
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Kinetics
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Magnetic Resonance Spectroscopy
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / chemistry*
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Metalloendopeptidases / metabolism*
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Metalloproteases / chemistry*
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Metalloproteases / metabolism*
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Models, Molecular
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Molecular Sequence Data
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Sequence Alignment
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Substrate Specificity / drug effects
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Tolloid-Like Metalloproteinases
Substances
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Bone Morphogenetic Proteins
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Enzyme Inhibitors
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Metalloproteases
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Tolloid-Like Metalloproteinases
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Metalloendopeptidases
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TLL1 protein, human
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TLL2 protein, human
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BMP1 protein, human
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Bone Morphogenetic Protein 1
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astacin