Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors.
The tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of the matrix metalloproteinases (MMPs), enzymes that play central roles in the degradation of extracellular matrix components. The balance between MMPs and TIMPs is important in the maintenance of tissues, and its disruption affects tissue homoeostasis. Four related TIMPs (TIMP-1 to TIMP-4) can each form a complex with MMPs in a 1:1 stoichiometry with high affinity, but their inhibitory activities towards different MMPs are not particularly selective. The three-dimensional structures of TIMP-MMP complexes reveal that TIMPs have an extended ridge structure that slots into the active site of MMPs. Mutation of three separate residues in the ridge, at positions 2, 4 and 68 in the amino acid sequence of the N-terminal inhibitory domain of TIMP-1 (N-TIMP-1), separately and in combination has produced N-TIMP-1 variants with higher binding affinity and specificity for individual MMPs. TIMP-3 is unique in that it inhibits not only MMPs, but also several ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with thrombospondin motifs) metalloproteinases. Inhibition of the latter groups of metalloproteinases, as exemplified with ADAMTS-4 (aggrecanase 1), requires additional structural elements in TIMP-3 that have not yet been identified. Knowledge of the structural basis of the inhibitory action of TIMPs will facilitate the design of selective TIMP variants for investigating the biological roles of specific MMPs and for developing therapeutic interventions for MMP-associated diseases.
Kennedy Institute of Rheumatology Division, Imperial College London, London W6 8LH, UK. h.nagase@imperial.ac.uk
Hideaki
H
Nagase
Keith
K
Brew
D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D019714:Tissue Inhibitor of Metalloproteinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases