Crystal structures of MMPs in complex with physiological and pharmacological inhibitors

Maskos, K.

doi:10.1016/j.biochi.2004.11.019

Cited by 187 publications

(280 citation statements)

References 82 publications

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“…This domain also contributes to proper substrate recognition, activation of the enzyme, protease localization, internalization and degradation 14 . The structures of the catalytic and hemopexin domains of several MMPs, including MMP1, MMP2, MMP3 and MMP14 (also known as membrane type 1 MMP (MT1-MMP)), have been solved (reviewed in REFS 13,15 ). MMP2 and MMP9 also have fibronectin type II repeats, which mediate binding to collagens, inserted into the catalytic domain.…”

Section: Mmp Proteolysismentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,585

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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Section: Mmp Proteolysismentioning

confidence: 99%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

2,585

2,180

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“…Interestingly, a glutamate in P1 was also instrumental in developing a peptide substrate with selectivity for MMP3 (58), which shares 78% overall amino acid identity with MMP10 and shows no significant structural differences in the catalytic domain (41). Notably, Ser 179 that our docking analysis identified as a potential hydrogen bonding partner for P1 glutamate residues is compared with other MMPs unique for MMP10 in this position (59). More in-depth analyses are needed, but this newly identified preference might be exploited for the development of more specific activity-based probes and inhibitors targeting MMP10 in cancer.…”

Section: Discussionmentioning

confidence: 96%

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

Schlage

Kockmann

Sabino

et al. 2015

Molecular & Cellular Proteomics

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“…Metalloproteinases represent a family of extracellular or membrane endopeptidases that are active in the presence of zinc and calcium ions, in neutral or slightly alkaline environment [7]. These enzymes are released in an inactive form and become activated within the intercellular space.…”

Section: Metalloproteinasesmentioning

confidence: 99%

“…TIMP binds non-covalently to a MMP molecule in a 1 : 1 ratio [1,2]. In this process, a specific role is played by the N-terminal domain, which chelates the atom of zinc via its amine group [7]. Additionally, the carboxyl group of N-terminal cysteine binds to zinc, blocking the activity of the entire enzyme [2].…”

Section: Metalloproteinase Inhibitorsmentioning

confidence: 99%

The role of extracellular matrix metalloproteinases and their inhibitors in allergic diseases

Kuźmiński¹,

Przybyszewski²,

Graczyk³

et al. 2012

pdia

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A b s t r a c tDuring the migration to the site of inflammation, allergic inflammatory cells must overcome several structures that constitute an impregnable barrier under normal conditions. One such structure is the extracellular matrix responsible for closely filling the intercellular space of tissues. The loosening of this tight structure by the activity of specific tissue enzymes, i.e. extracellular matrix metalloproteinases (MMPs), enables the influx of effector cells to the site of inflammation, thus facilitating the development of allergic inflammation and sustaining its presence. Specific tissue inhibitors of metalloproteinases (TIMPs) represent the most important factor involved in the regulation of MMP activity. Under physiological conditions, MMPs and TIMPs co-exist in a particular specific equilibrium, which is disturbed under pathological circumstances. The MMP-2 and MMP-9, referred to as gelatinases, belong to the best-studied MMPs associated with the development of allergic disorders. Their role pertains to the degradation of type IV collagen, the main component of basal membranes; this facilitates the influx of cells to the site of allergic inflammation. K Ke ey y w wo or rd ds s: : extracellular matrix, metalloproteinases, metalloproteinase inhibitors.

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Crystal structures of MMPs in complex with physiological and pharmacological inhibitors

Cited by 187 publications

References 82 publications

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix metalloproteinases and the regulation of tissue remodelling

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

The role of extracellular matrix metalloproteinases and their inhibitors in allergic diseases

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