Structural differences of matrix metalloproteinases. Homology modeling and energy minimization of enzyme-substrate complexes
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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 journal › Journal article › peer-review
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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 and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
SN - 0739-1102
IS - 6
ER -
ID: 38394303