Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes. / Terp, G E; Christensen, I T; Jørgensen, Flemming Steen.

In: Journal of Biomolecular Structure & Dynamics, Vol. 17, No. 6, 2000, p. 933-46.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Terp, GE, Christensen, IT & Jørgensen, FS 2000, 'Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes', Journal of Biomolecular Structure & Dynamics, vol. 17, no. 6, pp. 933-46.

APA

Terp, G. E., Christensen, I. T., & Jørgensen, F. S. (2000). Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes. Journal of Biomolecular Structure & Dynamics, 17(6), 933-46.

Vancouver

Terp GE, Christensen IT, Jørgensen FS. Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes. Journal of Biomolecular Structure & Dynamics. 2000;17(6):933-46.

Author

Terp, G E ; Christensen, I T ; Jørgensen, Flemming Steen. / Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes. In: Journal of Biomolecular Structure & Dynamics. 2000 ; Vol. 17, No. 6. pp. 933-46.

Bibtex

@article{9a086b231733456b8cfb95e1d759ecea,
title = "Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes",
abstract = "Matrix metalloproteinases are extracellular enzymes taking part in the remodeling of extracellular matrix. The structures of the catalytic domain of MMP1, MMP3, MMP7 and MMP8 are known, but structures of enzymes belonging to this family still remain to be determined. A general approach to the homology modeling of matrix metalloproteinases, exemplified by the modeling of MMP2, MMP9, MMP12 and MMP14 is described. The models were refined using an energy minimization procedure developed for matrix metalloproteinases. This procedure includes incorporation of parameters for zinc and calcium ions in the AMBER 4.1 force field, applying a non-bonded approach and a full ion charge representation. Energy minimization of the apoenzymes yielded structures with distorted active sites, while reliable three-dimensional structures of the enzymes containing a substrate in active site were obtained. The structural differences between the eight enzyme-substrate complexes were studied with particular emphasis on the active site, and possible sites for obtaining selectivity among the MMP's are discussed. Differences in the P1' pocket are well-documented and have been extensively exploited in inhibitor design. The present work indicates that selectivity could be further improved by considering the P2 pocket as well.",
keywords = "Amino Acid Sequence, Binding Sites, Calcium, Catalytic Domain, Crystallography, X-Ray, Databases, Factual, Humans, Ions, Ligands, Matrix Metalloproteinase 12, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Matrix Metalloproteinases, Membrane-Associated, Metalloendopeptidases, Microscopy, Electron, Models, Chemical, Models, Molecular, Molecular Sequence Data, Nitrogen, Protein Binding, Protein Structure, Secondary, Sequence Homology, Amino Acid, Zinc",
author = "Terp, {G E} and Christensen, {I T} and J{\o}rgensen, {Flemming Steen}",
year = "2000",
language = "English",
volume = "17",
pages = "933--46",
journal = "Journal of Biomolecular Structure & Dynamics",
issn = "0739-1102",
publisher = "Taylor & Francis",
number = "6",

}

RIS

TY - JOUR

T1 - Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes

AU - Terp, G E

AU - Christensen, I T

AU - Jørgensen, Flemming Steen

PY - 2000

Y1 - 2000

N2 - Matrix metalloproteinases are extracellular enzymes taking part in the remodeling of extracellular matrix. The structures of the catalytic domain of MMP1, MMP3, MMP7 and MMP8 are known, but structures of enzymes belonging to this family still remain to be determined. A general approach to the homology modeling of matrix metalloproteinases, exemplified by the modeling of MMP2, MMP9, MMP12 and MMP14 is described. The models were refined using an energy minimization procedure developed for matrix metalloproteinases. This procedure includes incorporation of parameters for zinc and calcium ions in the AMBER 4.1 force field, applying a non-bonded approach and a full ion charge representation. Energy minimization of the apoenzymes yielded structures with distorted active sites, while reliable three-dimensional structures of the enzymes containing a substrate in active site were obtained. The structural differences between the eight enzyme-substrate complexes were studied with particular emphasis on the active site, and possible sites for obtaining selectivity among the MMP's are discussed. Differences in the P1' pocket are well-documented and have been extensively exploited in inhibitor design. The present work indicates that selectivity could be further improved by considering the P2 pocket as well.

AB - Matrix metalloproteinases are extracellular enzymes taking part in the remodeling of extracellular matrix. The structures of the catalytic domain of MMP1, MMP3, MMP7 and MMP8 are known, but structures of enzymes belonging to this family still remain to be determined. A general approach to the homology modeling of matrix metalloproteinases, exemplified by the modeling of MMP2, MMP9, MMP12 and MMP14 is described. The models were refined using an energy minimization procedure developed for matrix metalloproteinases. This procedure includes incorporation of parameters for zinc and calcium ions in the AMBER 4.1 force field, applying a non-bonded approach and a full ion charge representation. Energy minimization of the apoenzymes yielded structures with distorted active sites, while reliable three-dimensional structures of the enzymes containing a substrate in active site were obtained. The structural differences between the eight enzyme-substrate complexes were studied with particular emphasis on the active site, and possible sites for obtaining selectivity among the MMP's are discussed. Differences in the P1' pocket are well-documented and have been extensively exploited in inhibitor design. The present work indicates that selectivity could be further improved by considering the P2 pocket as well.

KW - Amino Acid Sequence

KW - Binding Sites

KW - Calcium

KW - Catalytic Domain

KW - Crystallography, X-Ray

KW - Databases, Factual

KW - Humans

KW - Ions

KW - Ligands

KW - Matrix Metalloproteinase 12

KW - Matrix Metalloproteinase 2

KW - Matrix Metalloproteinase 9

KW - Matrix Metalloproteinases

KW - Matrix Metalloproteinases, Membrane-Associated

KW - Metalloendopeptidases

KW - Microscopy, Electron

KW - Models, Chemical

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Nitrogen

KW - Protein Binding

KW - Protein Structure, Secondary

KW - Sequence Homology, Amino Acid

KW - Zinc

M3 - Journal article

C2 - 10949161

VL - 17

SP - 933

EP - 946

JO - Journal of Biomolecular Structure & Dynamics

JF - Journal of Biomolecular Structure & Dynamics

SN - 0739-1102

IS - 6

ER -

ID: 38394303