An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

Crabbe, Thomas; Kelly, Sharon M.; Price, Nicholas C.

doi:10.1016/0014-5793(96)00005-1

Cited by 6 publications

(2 citation statements)

References 26 publications

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“…A distinct change in spectral features around 210 and 225 nm is observed upon inhibition of MMP-2 by both 1 and 2, this change corresponds to subtle reduction in the content of ␣-helixes, ␤-sheets, and ␤-turns. The CD spectra shown herein, is in agreement with previous CD studies (37). However, the evaluation of the changes in secondary structure should be treated with extreme caution in view of the relatively low molar ellipticities exhibited by MMP-2 (which is not dependent on protein concentration).…”

Section: Exafs Analysis Of Mmpssupporting

confidence: 90%

Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2)

Rosenblum

Meroueh

Kleifeld

et al. 2003

Journal of Biological Chemistry

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The zinc-dependent gelatinases belong to the family of matrix metalloproteinases (MMPs), enzymes that have been shown to play a key role in angiogenesis and tumor metastasis. These enzymes are capable of hydrolyzing extracellular matrix (ECM) components under physiological conditions. Specific and selective inhibitors aimed at blocking their activity are highly sought for use as potential therapeutic agents. We report herein on a novel mode of inhibition of gelatinase A (MMP-2) by the recently characterized inhibitors 4-(4-phenoxphenylsulfonyl)butane-1,2-dithiol (inhibitor 1) and 5-(4-phenoxphenylsulfonyl) pentane-1,2-dithiol (inhibitor 2). These synthetic inhibitors are selective for MMP-2 and MMP-9. We show that the dithiolate moiety of these inhibitors chelates the catalytic zinc ion of MMP-2 via two sulfur atoms. This mode of binding results in alternation of the coordination number of the metal ion and the induction of conformational changes at the microenvironment of the catalytic zinc ion; a set of events that is likely to be at the root of the potent slow binding inhibition behavior exhibited by these inhibitors. This study demonstrates a distinct approach for the understanding of the structural mechanism governing the molecular interactions between potent inhibitors and catalytic sites of MMPs, which may aid in the design of effective inhibitors.Matrix metalloproteinases (MMPs) 1 are major players in degradation of the extracellular matrix (ECM) components, and therefore they play key roles in normal and pathological conditions involving remodeling and turnover of ECM (1). MMPs constitute a multigene family of at least 26 secreted and membrane-tethered zinc-dependent endopeptidases, which can be classified according to their structures and substrate specificities (2, 3). Members of the family include: collagenases (MMP-1, -8, -13), gelatinases (MMP-2, -9), stromelysins , and membrane-type (MT)-MMPs (MT1-MMP to MT6-MMP). The catalytic domains of the MMPs have an ellipsoid shape with a small active site cleft. This cleft contains the catalytic zinc ion, which is essential for catalysis (4).Gelatinases, MMP-2 (gelatinase A) and MMP-9 (gelatinase B), constitute a distinct subgroup of the MMPs family due to the incorporation of three repeats of the fibronectin-type II module in the catalytic domain. These enzymes have been shown to play a key role in tumor cell invasion, metastasis, and angiogenesis by promoting degradation of ECM and the processing of cytokines, growth factors, hormones, and cell receptors (5, 6). As with other MMPs, MMP-2 and MMP-9 are expressed as zymogenic latent enzymes (pro-MMPs) requiring activation. Both proteolytic and non-proteolytic mechanisms have been described for zymogen activation. However, the "cysteine-switch" hypothesis (7) proposes that upon activation, the zinc ion in the latent active site is converted to a catalytic zinc ion by the dissociation of the conserved cysteine thiolate within the active site. The cleavage or the dissociation of the propeptide makes available ...

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Section: Exafs Analysis Of Mmpssupporting

confidence: 90%

Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2)

Rosenblum

Meroueh

Kleifeld

et al. 2003

Journal of Biological Chemistry

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“…93 The N‐terminal domain of the TIMPs appears to be the critical portion for inhibition, 94 although there is some enhancement of binding in the presence of the C‐domain. 95 The exception to the general rule is that TIMP‐1 appears to be a very poor inhibitor of MMP‐14 attached to the cell surface. 96 We now know from the recent work of Gomis‐Rüth et al 97 on the crystal structure of the MMP‐3/TIMP‐1 complex that TIMP acts as a chelator: the amino N and carbonyl oxygen of Cys‐1 chelate the zinc of the active site, while Thr‐2 and Val‐4 fit the binding pockets at S1′ and S2′.…”

Section: Tissue Inhibitors Of Metalloproteinases‐timpsmentioning

confidence: 99%

Matrix Metalloproteinase Inhibition: From The Jurassic To The Third Millennium

Woessner

1999

Annals of the New York Academy of Sciences

124

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A brief historical introduction to the matrix metalloproteinase (MMP) field, which began in 1962, is followed by an overview of the inhibition of these proteases by natural inhibitors such as alpha 2 macroglobulin and the TIMPs (tissue inhibitors of metalloproteinases) and by synthetic inhibitors, which are largely chelating agents. The latter include thiol, alkylcarbonyl, phosponamidate and hydroxamate compounds, as well as the tetracyclines. A review of the most recent progress concludes with prognostications as to where the field may be going next.

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Qualitative and quantitative protease activity tests based on protein degradation in three-dimensional structures

Göbel,

Müller,

Talke

et al. 2024

Bioelectrochemistry

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An analysis of the conformational changes that accompany the activation and inhibition of gelatinase A

Cited by 6 publications

References 26 publications

Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2)

Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2)

Matrix Metalloproteinase Inhibition: From The Jurassic To The Third Millennium

Qualitative and quantitative protease activity tests based on protein degradation in three-dimensional structures

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