Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor
Siân Rowsell1, Paul Hawtin, Claire A Minshull
1AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Abstract:
Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.
Insights
Matrix metalloproteinase 9 (MMP9) plays a key role in cardiovascular diseases like atherosclerosis and heart failure. Understanding its structure aids in designing specific inhibitors to treat these conditions.
Area of Science:
- Biochemistry
- Structural Biology
- Cardiovascular Research
Background:
- Matrix metalloproteinases (MMPs) are crucial in connective tissue remodeling, particularly in cardiovascular diseases such as atherosclerosis.
- MMP9 is consistently found in inflammatory atherosclerotic lesions and is implicated in plaque rupture and ventricular remodeling post-infarction.
- MMP9 activity is a potential key mechanism in the pathogenesis of heart failure.
Purpose of the Study:
- To determine the crystal structure of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor.
- To characterize the structural basis for MMP9 activity and its selectivity pocket.
- To facilitate the design of potent and specific MMP9 inhibitors for cardiovascular disease treatment.
Main Methods:
- X-ray crystallography was used to determine the structure of the catalytic domain of human MMP9.
- The structures were resolved at 2.3 Å and 2.1 Å for the inhibitor-bound wild-type and E402Q mutant forms, respectively.
- Analysis of the catalytic center and the S1' selectivity pocket was performed.
Main Results:
- The crystal structure of human MMP9 catalytic domain bound to a peptidic reverse hydroxamate inhibitor was determined.
- MMP9 exhibits a typical MMP fold with key residues (His 401, 405, 411, and Glu 402) forming the catalytic center.
- The S1' selectivity pocket of MMP9 is described as a tunnel, differing from other MMPs, which influences inhibitor design.
Conclusions:
- The determined structure provides crucial insights into the active site of MMP9.
- Structural information aids in the rational design of specific inhibitors targeting MMP9.
- This research supports the development of novel therapeutic strategies for cardiovascular diseases involving MMP9.
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