Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 angstrom resolution

The three-dimensional structure of human tissue inhibitor of metalloprotein ases-2 (TIMP-2) was determined by X-ray crystallography to 2.1 Angstrom res olution. The structure of the inhibitor consists of two domains. The N-term inal domain (residues 1-110) is folded into a beta-barrel, similar to the o ligonucleotide/oligosaccharide binding fold otherwise found in certain DNA- binding proteins. The C-terminal domain (residues 111-194) contains a paral lel stranded beta-hairpin plus a beta-loop-beta motif. Comparison of the st ructure of uncomplexed human TIMP-2 with that of bovine TIMP-2 bound to the catalytic domain of human MMP-14 suggests an internal rotation between the two domains of similar to 13 degrees upon binding to the protease. Further more, local conformational differences in the two structures that might be induced by formation of the protease-inhibitor complex have been found. The most prominent of these involves residues 27-40 of the A-B beta-hairpin lo op. Structure-based alignment of amino acid sequences of representatives of the TIMP family maps the sequence differences mainly to loop regions, and some of these differences are proposed to be responsible for the particular properties of the various TIMP species. (C) 1998 Academic Press.