Structural basis for the substrate specificity of bone morphogenetic protein 1/tolloid-like metalloproteases.
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.
Mac Sweeney
A
A
Center for Proteomic Chemistry, Novartis Institute for Biomedical Research, Novartis Campus, CH-4002 Basel, Switzerland. aengus.mac_sweeney@novartis.com
Gil-Parrado
S
S
Vinzenz
D
D
Bernardi
A
A
Hein
A
A
Bodendorf
U
U
Erbel
P
P
Logel
C
C
Gerhartz
B
B
D000595:Amino Acid Sequence; D000818:Animals; D003400:Astacoidea / Q000201:enzymology; D001665:Binding Sites; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D045726:Metalloproteases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013379:Substrate Specificity / Q000187:drug effects; D055394:Tolloid-Like Metalloproteinases
D019485:Bone Morphogenetic Proteins; D004791:Enzyme Inhibitors; D045726:Metalloproteases; D055394:Tolloid-Like Metalloproteinases; D008666:Metalloendopeptidases; C484478:TLL1 protein, human; C485669:TLL2 protein, human; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1; C071288:astacin