Figure 1
From: Towards third generation matrix metalloproteinase inhibitors for cancer therapy
Sequence alignment of every human MMP active site. (A) The amino-acid sequences of MMP catalytic domain regions containing the S1′ subsite forming residues (red frame) and S2 essential residues (blue frame) were aligned using T-Coffee (Notredame C, Higgins DG, Heringa J (2000) T-Coffee: a novel method for fast and accurate multiple sequence alignment. J Mol Biol 302: 205–217) and annotated using ESPrint (Gouet P, Courcelle E, Stuart DI, Metoz F (1999) ESPript: analysis of multiple sequence alignments in PostScript. Bioinformatics 15: 305–308). The secondary structure and numbering is based on MMP1 Protein Data bank (PDB) #1HFC. (B) Structural representation of antitarget MMPs. The catalytic domains of MMP3 (PDB:1CIZ), MMP8 (PDB: 1KBC), MMP9 (PDB:1GKD) and MMP12 (PDB: 1Y93) were structurally aligned and superimposed. The empty voids of the catalytic pockets were calculated using CASTp (Liang J, Edelsbrunner H, Woodward C (1998) Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. Protein Sci 7: 1884–1897) and visualised using Pymol (DeLano Scientific LLC, San Francisco, CA, USA http://www.pymol.org/) and its CATSp plugin. The S1′ pocket voids are in yellow, the essential S2 pocket residues at position 227 are shown in blue, and the S1′ specificity loop is shown in orange-red. The original structures contained a bound inhibitor in the active site, which was removed prior to calculation. Therefore, the S1′ voids include any structural adaptations in the molecule that were needed to accommodate the inhibitor. Although, these adaptations occurred upon binding of different inhibitors, the character of the void spaces is quite similar (data not shown).
