An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A.
The latent precursors of the matrix metalloproteinases (MMPs) are converted by (4-aminophenylmercuric)acetate to active forms that lose their propeptide as a result of autolysis. C.D. and an active site mutant of progelatinase A (MMP2) were used to demonstrate that, although propeptide removal is accompanied by a decrease in the enzyme's beta-sheet content, the initial activation is achieved with only minor modifications to the conformation. Mixing activated gelatinase A with the natural inhibitor, TIMP-1, resulted in conformational changes that were absent when a synthetic inhibitor was used. The relevance of these results to MMP activation and inhibition is discussed.
Crabbe
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Discovery Projects, Celltech Therapeutics Ltd., Slough, UK.
Kelly
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SM
Price
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NC
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D004789:Enzyme Activation / Q000187:drug effects; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D011480:Protease Inhibitors; D011498:Protein Precursors; D019714:Tissue Inhibitor of Metalloproteinases; C010024:4-aminophenylmercuriacetate; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D010662:Phenylmercuric Acetate