Sandbox Reserved 1125: Difference between revisions
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== Mechanism == | == Mechanism == | ||
To express collagenolytic activity, MMP-8 needs to have both the catalytic and hemopexin domains but it is not clear how the hemopexin domain help to cleave triple-helical collagens because it does not bind to collagen.<ref>PMID:8489511</ref> Moreover, MMP-8 is secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases. Indeed, it can't be activated without removal of the activation peptide. But recent evidences suggest that this protease activation is blocked by the formation of an intramolecular complex between the propeptide domain on the Cysteine residue and essential zinc atom in the catalytic domain. It is called the ''Cysteine-switch''. This discovery is unprecedented in enzymology and offers the opportunity for multiple modes of physiological activation of | To express collagenolytic activity, MMP-8 needs to have both the catalytic and hemopexin domains but it is not clear how the hemopexin domain help to cleave triple-helical collagens because it does not bind to collagen.<ref>PMID:8489511</ref> Moreover, MMP-8 is secreted as inactive proproteins and then activated after a cleavage by extracellular proteinases. Indeed, it can't be activated without removal of the activation peptide. But recent evidences suggest that this protease activation is blocked by the formation of an intramolecular complex between the propeptide domain on the Cysteine residue and essential zinc atom in the catalytic domain. It is called the ''Cysteine-switch''. This discovery is unprecedented in enzymology and offers the opportunity for multiple modes of physiological activation of MMP-8. Moreover, since conditions in different cells and tissues may match those necessary to effect one of these activation modes for a given MMP, this may offer metabolic flexibility in the control of MMP activation.<ref>PMID:2164689</ref> | ||
To allow cleavage of the individual alpha chains of collagen, the binding of activated MMP-8 must partially unwind triple helix by inducing a conformational change in alpha chain. However, the molecular basis of this mechanism is not known.<ref>PMID:6270090</ref> | |||
To allow cleavage of the individual alpha chains of collagen, the binding of | |||
The carbonyl group of the peptide bond coordinates with the active-site zinc. This displaces the water molecule from the zinc atom. The peptide hydrolysis is assisted by the carboxyl group of the glutamate, which serves as a general base to draw a proton from the displaced water molecule, thereby facilitating the nucleophilic attack of the water molecule on the carbonyl carbon of the peptide scissile bond. A pocket to the right of the active-site zinc, called the specificity pocket or <scene name='71/719866/S1prime_pocket/1'>S1' pocket</scene>, accommodates the side chain of the substrate residue, which becomes the new N-terminus after cleavage. The sizes of the S1′ pocket vary among the MMPs, and this is one of the major determining factors of substrate specificity.<ref>PMID:12730128</ref> | The carbonyl group of the peptide bond coordinates with the active-site zinc. This displaces the water molecule from the zinc atom. The peptide hydrolysis is assisted by the carboxyl group of the glutamate, which serves as a general base to draw a proton from the displaced water molecule, thereby facilitating the nucleophilic attack of the water molecule on the carbonyl carbon of the peptide scissile bond. A pocket to the right of the active-site zinc, called the specificity pocket or <scene name='71/719866/S1prime_pocket/1'>S1' pocket</scene>, accommodates the side chain of the substrate residue, which becomes the new N-terminus after cleavage. The sizes of the S1′ pocket vary among the MMPs, and this is one of the major determining factors of substrate specificity.<ref>PMID:12730128</ref> | ||
