Dataset Information

Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

ABSTRACT: Matrix metaloproteinase-2 (MMP-2) is an extracellular Zn2+ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed ten families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamic cross-correlation analysis indicated domain movements corresponding to the opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the molecular mechanics Poisson Boltzman surface area-interaction entropy (MMPBSA-IE) analysis method and revealed strong binding energies for the catalytic Zn2+ ion 1, Ca2+ ion 1, and Ca2+ ion 3 with significant conformational stability at the binding sites of Zn2+ ion 1 and Ca2+ ion 1. Ca2+ ion 2 diffuses freely away from its crystallographically defined binding site. Zn2+ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca2+ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central ?-sheet core of the hemopexin domain; however, the interacting residue sidechain carboxyl groups are outside of Ca2+ ion 3's coordination sphere.

SUBMITTER: Voit-Ostricki L

PROVIDER: S-EPMC6747341 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

Voit-Ostricki Leah L Lovas Sándor S Watts Charles R CR

International journal of molecular sciences 20190827 17

Matrix metaloproteinase-2 (MMP-2) is an extracellular Zn2+ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed ten families of conformations with the greatest degree of variability oc ...[more]

PMID: 31461891

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Project description:ObjectivesMatrix metalloproteinase-8 messenger RNA expression was previously found to be increased in whole blood of children with septic shock. The impact of this finding on the severity and inflammatory response to sepsis is unknown. Here, we investigate the relationship between matrix metalloproteinase-8 and disease severity in children with septic shock. We further corroborate the role of matrix metalloproteinase-8 in sepsis in a murine model.DesignRetrospective observational clinical study and randomized controlled laboratory experiments.SettingPediatric intensive care units and an animal research facility at an academic children's hospital.Patients and subjectsPatients age ≤10 yrs admitted to the intensive care unit with a diagnosis of septic shock. For laboratory studies, we utilized male mice deficient for matrix metalloproteinase-8 and male wild-type C57BL/6J mice.InterventionsBlood from children with septic shock was analyzed for matrix metalloproteinase-8 messenger RNA expression and matrix metalloproteinase-8 activity, and correlated with disease severity based on mortality and degree of organ failure. A murine model of sepsis was used to explore the effect of genetic and pharmacologic inhibition of matrix metalloproteinase-8 on the inflammatory response to sepsis. Finally, activation of nuclear factor-κB was assessed both in vitro and in vivo.Measurements and main resultsIncreased matrix metalloproteinase-8 mRNA expression and activity in septic shock correlates with decreased survival and increased organ failure in pediatric patients. Genetic and pharmacologic inhibition of matrix metalloproteinase-8 leads to improved survival and a blunted inflammatory profile in a murine model of sepsis. We also identify matrix metalloproteinase-8 as a direct in vitro activator of the proinflammatory transcription factor, nuclear factor-κB.ConclusionsMatrix metalloproteinase-8 is a novel modulator of inflammation during sepsis and a potential therapeutic target.

Dataset Information

Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

Publications

Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn<sup>2+</sup> and Ca<sup>2+</sup> Ions.

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