Structure-based development of a novel collagen inhibitor for MMP-1: re-designing the functions of a matrix protein.
Collagenases are a highly specific class of enzymes. In their native states, collagenases cleave only native triple helical collagen molecules at a single peptide bond between Gly775-Leu776 for Type I collagen and Gly775-Ile776 for Type II collagen. The linear sequence of collagen is about 1050 amino acids in length, where three linear peptide sequences are required to form a triple helical collagen molecule. At present, there exist no crystallographic structures of collagenase bound to native triple helical collagen; nor has it been shown that collagenase recognizes the triple helical conformation of collagen. In our study, we have used an inhibitor design structure-activity based approach to show that collagenase recognizes and cleaves triple helical collagen conformations in preference to non-triple helical collagen conformations.
Chen
James M
JM
Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. jchen@gilead.com
Yeh
Li-An
LA
D000818:Animals; D001168:Arthritis / Q000378:metabolism; D002384:Catalysis; D003094:Collagen / Q000737:chemistry*; D017364:Collagenases / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D012984:Software; D013552:Swine
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D003094:Collagen; D017364:Collagenases; D020781:Matrix Metalloproteinase 1