Matrix Metalloproteinases: From Structure to Function

Stawikowski, Maciej; Fields, Gregg B.

doi:10.1002/9781118772287.ch1

Cited by 3 publications

(4 citation statements)

References 141 publications

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“…In the X-ray crystallographic structure His209 formed hydrogen bonds with the side chain of Gln774(L) while A165 had no interactions with the THP. The carbonyl group of Ala165 has been proposed to be involved in MMP-1 catalyzed collagen hydrolysis by stabilizing the positive charge at the nitrogen of the scissile bond . The residues in the vicinity of the scissile bond of the THP L strand are stabilized to a greater extent in the NMR-based structure compared with the X-ray crystallographic structure.…”

Section: Resultsmentioning

confidence: 99%

Conformational Dynamics of Matrix Metalloproteinase-1·Triple-Helical Peptide Complexes

Karabencheva‐Christova

Christov

Fields

2017

J. Phys. Chem. B

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Matrix metalloproteinase-1 (MMP-1) is a zinc-dependent protease that catalyzes hydrolysis of interstitial collagens. A previously reported X-ray crystallographic structure revealed specific interactions between a triple-helical peptide (THP) model of interstitial collagen and the hemopexin-like (HPX) and catalytic (CAT) domains of MMP-1. An NMR-based structure of MMP-1 in a complex with a different THP was also solved, where docking was used to model the MMP-1·THP interactions and develop a mechanism for the early stages of collagenolysis. To provide greater insight into and reveal specific details of the collagenolytic mechanism, molecular dynamics (MD) studies of the MMP-1·THP NMR-derived and X-ray crystallographic complexes were performed and compared. The "open/extended" conformation of the NMR-derived MMP-1·THP complex was found to lead to a catalytically productive complex. The X-ray crystallographic MMP-1·THP complex was initially in a "closed/collapsed" conformation, and did not yield a productive complex. The NMR-derived structure of the MMP-1·THP complex possessed many more atomistic interactions between MMP-1 and the THP compared with the X-ray crystallographic structure of the MMP-1·THP complex, and also had greater participation of MMP-1 in the local unwinding/destabilization of the THP. The atomistic interactions support the favorable energetics of the initial step of collagenolysis originating from the NMR-derived MMP-1·THP complex structure.

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Section: Resultsmentioning

confidence: 99%

Conformational Dynamics of Matrix Metalloproteinase-1·Triple-Helical Peptide Complexes

Karabencheva‐Christova

Christov

Fields

2017

J. Phys. Chem. B

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“…The linker region in MMP-13 is the same size as the linker in MMP-1, but with a different sequence 42 . The RMSD profile of MMP-1 with the linker of MMP-13 (MMP-1/MMP-13) showed that the system equilibrated at ~20 nsec (Figure 2) and indicated that MMP-1/MMP-13 had greater structural deviation with average value of 5.3 Å in comparison to MMP-1 (4.7 Å).…”

Section: Resultsmentioning

confidence: 99%

“…9,14,15 In order to explore the effects of the nature of the MMP-1 linker region (both the length of the linker and its amino acid sequence) on modulating domain interactions, it was exchanged with the linker region from MMP-14 (which contains 35 residues compared with 17 residues in MMP-1) or MMP-13 (which consists of the same number of residues as the MMP-1 linker but with a different sequence). 42 The trajectory of MMP-1 with in silico MMP-14 linker (MMP-1/MMP-14) showed that the system equilibrated at $20 ns (Fig. S11 †).…”

Section: Triple-helix Interactions With the Cat And Hpx Domainsmentioning

confidence: 99%

Importance of the linker region in matrix metalloproteinase-1 domain interactions

et al. 2016

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Collagenolysis is catalyzed by enzymes from the matrix metalloproteinase (MMP) family, where one of the most studied is MMP-1. The X-ray crystallographic structure of MMP-1 complexed with a collagen-model triple-helical peptide (THP) provided important atomistic information, but few details on the effects of the conformational flexibility on catalysis. In addition, the role of the linker region between the catalytic (CAT) and hemopexin-like (HPX) domains was not defined. In order to reveal the dynamics and correlations of MMP-1 comprehensive atomistic molecular dynamics simulations of an MMP-1•THP complex was performed. To examine the role of the linker region for MMP-1 function simulations with linker regions from MT1-MMP/MMP-14 and MMP-13 replacing the MMP-1 linker region were performed. The MD studies were in good agreement with the experimental observation that in the MMP-1•THP X-ray crystallographic structure MMP-1 is in a “closed” conformation. MD revealed that the interactions of the THP with the both the CAT and HPX domains of MMP-1 are dynamic in nature, and the linker region of MMP-1 influences the interactions and dynamics of both the CAT and HPX domains and collagen binding to MMP-1.

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“…9 Matrix metalloproteinases (MMPs) are members of zincendopeptidases that regulate cell matrix composition and can degrade extracellular matrix. 10 MMPs are composed of 25 enzymes, divided into collagenases, gelatinases, stromelysins, matrilysins or membrane-type MMPs. MMP3, member of stromelysins, is responsible for extracellular matrix remodeling and degradation, cell proliferation, and angiogenesis.…”

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MMP3 single‐nucleotide polymorphisms are associated with noncontact ACL injuries in competing high‐level athletes

Briški

Vrgoč

Knjaz

et al. 2023

Journal Orthopaedic Research

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Matrix metalloproteinases (MMPs) play an important role in matrix remodeling, as well as in ligament integrity. Anterior cruciate ligament (ACL) rupture is a severe and frequent knee injury in sports. The aim of this study was to investigate polymorphisms within the MMP3 gene with the predisposition for noncontact ACL rupture in the Croatian professional athletes. One hundred eighty‐seven (95 with ACL rupture occurring through a noncontact mechanism and 92 asymptomatic controls) unrelated Caucasians were recruited between 2016 and 2017. All participants were genotyped for three single‐nucleotide polymorphisms (SNP) within the MMP3 gene: rs591058 C/T, rs650108 A/G, and rs679620 G/A using the pyrosequencing method. For all three investigated SNPs, genotype frequencies have significantly differed between cases and controls. The MMP3 rs591058 TT (p = 0.0012, odds ratio [OR] = 38.541, 95% confidence interval [CI] = 1.7024–8.7254), rs650108 GG (p = 0.0051, OR = 23.338, 95% CI = 1.2899–4.2226) and rs679620 AA (p = 0.0030, OR = 34.750, 95% CI = 1.5266–7.9101) genotypes, as well as haplotype variant T‐G‐A (p = 0.0104, OR = 1.71, 95% CI = 1.13–2.59) were significantly overrepresented in cases compared to controls. These results support association between functional variants within the MMP3 gene and the risk of ACL rupture. Still, further research is needed to corroborate these results in a larger population.

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Matrix Metalloproteinases: From Structure to Function

Cited by 3 publications

References 141 publications

Conformational Dynamics of Matrix Metalloproteinase-1·Triple-Helical Peptide Complexes

Conformational Dynamics of Matrix Metalloproteinase-1·Triple-Helical Peptide Complexes

Importance of the linker region in matrix metalloproteinase-1 domain interactions

MMP3 single‐nucleotide polymorphisms are associated with noncontact ACL injuries in competing high‐level athletes

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