NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases.
A high quality solution structure of the matrix metalloproteinase inhibitory N-terminal domain of recombinant human tissue inhibitor of metalloproteinases-1 (N-TIMP-1) has been determined. For the rigidly packed residues, the average RMSD to the mean structure is 0. 57 A for the backbone atoms and 1.00 A for all heavy atoms. Comparison of the solution structure of free N-TIMP-1 with the crystal structure of TIMP-1 bound to the catalytic domain of MMP-3 ( Gomis-R]uth et al., 1997 ) shows that the structural core of the beta barrel flanked by helices is nearly unchanged by the association with MMP-3, evident from a backbone RMSD of 1.15 A. However, clear differences in the conformation of the MMP-binding ridge of free and MMP-bound TIMP-1 suggest induced fit throughout the ridge. The MMP-dependent conformational changes in the ridge include a dramatic bending of AB loop residues Glu28 through Leu34, moderate hinge bending of the CD-loop about residues Ala65 and Cys70, and modest bending of the Cys1 through Pro6 segment. A large number of interresidue Nuclear Overhauser enhancements (NOEs) augmented by stereospecific assignments, torsion restraints, and dipolar couplings (an average of 18 non-trivial restraints per residue) engender confidence in these structural inferences. A tight cluster of three lysine residues and one arginine residue atop beta-strands A and B, and identical among TIMP sequences, form the heart of a highly conserved electropositive patch that may interact with anionic components of the extracellular matrix.
Wu
B
B
Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA.
Arumugam
S
S
Gao
G
G
Lee
G I
GI
Semenchenko
V
V
Huang
W
W
Brew
K
K
Van Doren
S R
SR
D020134:Catalytic Domain; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000737:chemistry* / Q000378:metabolism
D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases