Structure-based development of a novel collagen inhibitor for MMP-1: re-designing the functions of a matrix protein.

Abstract

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.