Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1

Gomis-Rüth, Franz-Xaver; Maskos, K.; Betz, Michael; Bergner, Andreas; Huber, Robert; Suzuki, Ko; Yoshida, Naoki; Nagase, Hideaki; Brew, Keith; Bourenkov, Gleb; Bartunik, H.D.; Bode, Wolfram

doi:10.1038/37995

Cited by 575 publications

(515 citation statements)

References 4 publications

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“…Previously we have shown for a cdMMP-3-TIMP-1 59 and for a cdMT1-MMP-TIMP-2 complex 25 that the wedgeshaped TIMPs bind with their flexible edge consisting of six loops/segments into the entire active-site cleft of their cognate MMPs. The TIMPs mainly interact through their N-term-inal segment and the disulfide connected C-D loop, but make a number of contacts through the peripheral sA-sB loop and the two C-terminal loops.…”

Section: Timp-1 Docking To Mt-mmps Shows Obstacles For Interactionmentioning

confidence: 99%

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Lang

Braun

Sounni

et al. 2004

Journal of Molecular Biology

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Membrane-type matrix metalloproteinases (MT-MMPs) have attracted strong attention, because four of them can activate a key player in the tumor scenario, proMMP-2/progelatinase A. In addition to this indirect effect on the cellular environment, these MT-MMPs degrade extracellular matrix proteins, and their overproduction is associated with tumor growth. We have solved the structure of the catalytic domain (cd) of MT3-MMP/MMP-16 in complex with the hydroxamic acid inhibitor batimastat. CdMT3-MMP exhibits a classical MMP-fold with similarity to MT1-MMP Nevertheless, it also shows unique properties such as a modified MT-specific loop and a closed S1' specificity pocket, which might help to design specific inhibitors. Some MT-MMP-specific features, derived from the crystal structures of MT-1-MMP determined previously and MT3-MMP, and revealed in recent mutagenesis experiments, explain the impaired interaction of the MT-MMPs with TIMP-1. Docking experiments with proMMP-2 show some exposed loops including the MT-loop of cdMT3-MMP involved in the interaction with the proMMP-2 pro-domain in the activation encounter complex. This model might help to understand the experimentally proven importance of the MT-loop for the activation of proMMP-2.

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Section: Timp-1 Docking To Mt-mmps Shows Obstacles For Interactionmentioning

confidence: 99%

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Lang

Braun

Sounni

et al. 2004

Journal of Molecular Biology

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“…Three-dimensional structures of human TIMP-1 and TIMP-2 in complex with metalloproteinase targets have recently been determined by x-ray crystallography and NMR spectroscopy, respectively (38,39). The common structure of the C345C/NTR domain consists of a five-stranded ␤ barrel and two terminal ␣ helices packed side by side against the barrel face.…”

Section: Structure Of the Binding Sitementioning

confidence: 99%

Distal Recognition Site for Classical Pathway Convertase Located in the C345C/Netrin Module of Complement Component C5

Sandoval

Ostresh

et al. 2000

The Journal of Immunology

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Previous studies focused on indels in the complement C345 protein family identified a number of potential protein-protein interaction sites in components C3 and C5. Here, one of these sites in C5, near the α-chain C terminus, was examined by alanine-scanning mutagenesis at 16 of the 18 non-alanine residues in the sequence KEALQIKYNFSFRYIYPLD. Alanine substitutions affected activities in the highly variable manner characteristic of binding sites. Substitutions at the lysine or either phenylalanine residue in the central KYNFSF sequence had the greatest effects, yielding mutants with <20% of the normal activity. These three mutants were also resistant to the classical pathway (CP) C5 convertase, with sensitivities roughly proportional to their hemolytic activities, but had normal susceptibilities to the cobra venom factor (CVF)-dependent convertase. Synthetic peptide MGKEALQIKYNFS-NH2 was found similarly to inhibit CP but not CVF convertase activation, and the effects of alanine substitutions in this peptide largely reflected those of the equivalent mutations in C5. These results indicate that residues KYNFSF form a novel, distal binding site for the CP, but not CVF convertase. This site lies ∼880 residues downstream of the convertase cleavage site within a module that has been independently named C345C and NTR; this module is found in diverse proteins including netrins and tissue inhibitors of metalloproteinases.

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“…1,2 Stromelysin-1 is a key member of the matrix metalloproteinase family and has a wide substrate specificity. 3 Stromelysin expression is regulated primarily at the level of transcription, where the promoter of the gene responds to different stimuli including growth factors and cytokines. 4 Recently, a common variant in the promoter sequence of the stromelysin-1 gene has been reported.…”

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confidence: 99%

Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis

Rauramaa

Väisänen²,

Luong³

et al. 2000

ATVB

193

109

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Abstract-The functional 5A/6A polymorphism of the stromelysin-1 promoter has been implicated as a potential genetic marker for the progression of angiographically determined atherosclerosis in patients with coronary artery disease. Recently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at Ϫ174 in the promoter has also been reported. In this study, we analyzed the relation of these two polymorphisms with carotid artery atherosclerosis in 109 randomly selected, middle-aged men without exercise-induced ischemia. Atherosclerosis was quantified as intimamedia thickness (IMT) by high-resolution ultrasonography. Univariately, stromelysin genotype was significantly (Pϭ0.015) associated with IMT, and this relation remained (Pϭ0.033) after adjustments for age, cardiorespiratory fitness, body mass index, smoking, LDL cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcation IMT. The IL-6 polymorphism was also significantly associated (Pϭ0.036) with increased IMT, with men homozygous for the G allele having IMT that was 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% greater than men who were homozygous for neither allele (PϽ0.003). These data suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) combine to increase susceptibility for intima-media thickening in the carotid bifurcation, a predilection site for atherosclerosis. Key Words: stromelysin-1 Ⅲ interleukin-6 Ⅲ DNA polymorphism Ⅲ B-mode ultrasonography Ⅲ carotid atherosclerosis Ⅲ population sample

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Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1

Cited by 575 publications

References 4 publications

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Crystal Structure of the Catalytic Domain of MMP-16/MT3-MMP: Characterization of MT-MMP Specific Features

Distal Recognition Site for Classical Pathway Convertase Located in the C345C/Netrin Module of Complement Component C5

Stromelysin-1 and Interleukin-6 Gene Promoter Polymorphisms Are Determinants of Asymptomatic Carotid Artery Atherosclerosis

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