Structural Differences of Matrix Metalloproteinases. Homology Modeling and Energy Minimization of Enzyme-Substrate Complexes

• Published in: Journal of biomolecular structure & dynamics 2000-06, Vol.17 (6), p.933-946
• Main Authors: Terp, Gitte Elgaard, Christensen, Inge Thøger, Jørgensen, Flemming Steen
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Calcium - chemistry; Catalytic Domain; Crystallography, X-Ray; Databases, Factual; Humans; Ions; Ligands; Matrix Metalloproteinase 12; Matrix Metalloproteinase 2 - chemistry; Matrix Metalloproteinase 9 - chemistry; Matrix Metalloproteinases - chemistry; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases - chemistry; Microscopy, Electron; Models, Chemical; Models, Molecular; Molecular Sequence Data; Nitrogen - chemistry; Protein Binding; Protein Structure, Secondary; Sequence Homology, Amino Acid; Zinc - chemistry
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2000.10506582

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.