Engineering of selective TIMPs.

H Nagase; Q Meng; V Malinovskii; W Huang; L Chung; W Bode; K Maskos; K Brew

doi:10.1111/j.1749-6632.1999.tb07670.x

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PubMed · 10415716

Engineering of selective TIMPs.

H Nagase·Q Meng·V Malinovskii·W Huang·L Chung·W Bode·K Maskos·K Brew

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Abstract

Differences in proteinase susceptibility between free TIMP-1 and the TIMP-1-MMP-3 complex and mutagenesis studies suggested that the residues around the disulfide bond between Cys1 and Cys70 in TIMP-1 may interact with MMPs. The crystal structure of the complex between TIMP-1 and the catalytic domain of MMP-3 has revealed that the alpha-amino group of Cys1 bidentately chelates the catalytic zinc of MMP-3 and the Thr2 side chain occupies the S1' pocket. Generation of the N-terminal domain of TIMP-1 (N-TIMP-1) variants with 15 different amino acid substitutions for Thr2 has indicated that the nature of the side chain of residue 2 has a major effect on the affinity of N-TIMP-1 for three different MMPs (MMPs-1, -2 and -3). The results also demonstrate that the mode of binding of N-TIMP-1 residue 2 differs from the binding of the P1' residue of a peptide substrate.

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Amino Acid Sequence Animals Humans Kinetics Metalloendopeptidases Mutagenesis Protein Engineering Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Journal Article Research Support, U.S. Gov't, P.H.S.Review

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H Nagase, Q Meng, V Malinovskii, W Huang, L Chung, W Bode, K Maskos, K Brew. 1999-06-30. Engineering of selective TIMPs.. https://doi.org/10.1111/j.1749-6632.1999.tb07670.x

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