Insights into MMP-TIMP interactions.
The proteolytic activity of the matrix metalloproteinases (MMPs) involved in extracellular matrix degradation must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance can result in serious diseases such as arthritis and tumor growth and metastasis. Knowledge of the tertiary structures of the proteins involved in such processes is crucial for understanding their functional properties and to interfere with associated dysfunctions. Within the last few years, several three-dimensional structures have been determined showing the domain organization, the polypeptide fold, and the main specificity determinants of the MMPs. Complexes of the catalytic MMP domains with various synthetic inhibitors enabled the structure-based design and improvement of high-affinity ligands, which might be elaborated into drugs. Very recently, structural information also became available for some TIMP structures and MMP-TIMP complexes, and these new data elucidated important structural features that govern the enzyme-inhibitor interaction.
Bode
W
W
Max-Planck-Institut für Biochemie, Martinsried, Germany. bode@biochem.mpg.de
Fernandez-Catalan
C
C
Grams
F
F
Gomis-Rüth
F X
FX
Nagase
H
H
Tschesche
H
H
Maskos
K
K
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000737:chemistry; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000737:chemistry; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry; D019714:Tissue Inhibitor of Metalloproteinases / Q000737:chemistry* / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D008666:Metalloendopeptidases