Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases

J Mol Biol. 2008 Dec 5;384(1):228-39. doi: 10.1016/j.jmb.2008.09.029. Epub 2008 Sep 19.


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

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


  • Bone Morphogenetic Proteins
  • Enzyme Inhibitors
  • Metalloproteases
  • Tolloid-Like Metalloproteinases
  • Metalloendopeptidases
  • TLL1 protein, human
  • TLL2 protein, human
  • BMP1 protein, human
  • Bone Morphogenetic Protein 1
  • astacin