Similarity of Binding Sites of Human Matrix Metalloproteinases

Abstract

Tissue components hydrolyzing matrix metalloproteinases (MMPs) exhibit a high sequence similarity (56 -64% in catalytic domains) and yet a significant degree of functional specificity. The hexapeptide-binding sites of 24 known human MMPs were compared in terms of their force field interaction energies with five probes that are most frequently encountered in substrates and inhibitors. The probes moved along a grid enclosing partially flexible binding sites in rigid catalytic domains that were represented by published experimental structures and comparative models and new comparative models for nine most recently characterized MMPs. For individual MMPs, representative interaction energies were obtained as averages for all suitable experimental structures. Correlations of the representative energies for all MMP pairs were succinctly catalogued for individual probes, subsites, and correlation levels. Among the probes (neutral sp 3 carbon and sp 3 oxygen, positive sp 3 nitrogen and hydrogen, and negative carbonyl oxygen), the last probe is least distinctive. Similarities of subsites are decreasing as S1 > S2 > S3 > S1 ϳ S3 > S2 . Most interesting, occupancies of subsites in published structures of MMP-inhibitor complexes follow an almost parallel trend, alluding to overall low selectivity of known MMP inhibitors. Flexible subsite S1 that appears as the specificity pocket in rigid x-ray structures is actually very similar among individual MMPs. Several correlations indicated that MMPs 3, 8, and 12 have similar binding sites. Modeling results are corroborated with published experimental data on MMP inhibition and substrate specificities. The results provide numerous clues for development of specific inhibitors and substrates, as well as for selection of MMPs for testing that provides maximum information without redundant experiments.

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

“…Nonetheless, most MMPIs lack specificity with only a few able to spare the shallow S 1 0 pocket MMPs by incorporating bulky or long side chains at P 1 0 (Overall and Kleifeld, 2006). Perhaps not surprisingly, the antitarget MMPs 3, -8, -9 and also -12, a potential antitarget (Overall and Kleifeld, 2006), have similar binding properties in the active site (Lukacova et al, 2004). Comparative modeling reveals that the void volumes of the MMP antitarget S 1 0 pockets are very similar in size and shape ( Figure 1B).…”

A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor-α Converting Enzyme: Implications for Selectivity

“…Remaining MMPs were superimposed on MMP-7 as described previously. 31 Superimposed TACE and MMP-7 structures exhibit an almost perfect overlap of the backbones in individual subsites, except S3 subsite (Figure 2). However, the residues forming individual subsites have considerable effect on the overall shapes of the binding sites.…”

“…The probe was placed in each of the grid points, and the Tripos force-field interaction energy35 , 36 was calculated for individual partially flexible binding sites. 31 The interaction energies were compared with two goals: (i) to identify the MMPs and their subsites that are most similar to TACE and (ii) to delineate the properties of the regions responsible for specific interactions of TACE with individual probes.…”

Identification of New Snake Venom Metalloproteinase Inhibitors Using Compound Screening and Rational Peptide Design

“…4−9 Most MMP inhibitors to date developed consist of a zinc-binding group (ZBG), which binds the catalytic metal ion, 5,8,10 and a peptidomimetic backbone, which interacts noncovalently with the active site of the enzyme. 7,11 The peptidomimetic Batimastat (BB-94) is a first generation MMP inhibitor that contains the most common ZBG, that is, a hydroxamate moiety.Because of the difficulty in neutralizing locally acting SVMPs by antivenoms, the possibility has been raised that specific enzyme inhibitors may represent a new alternative for the treatment of these envenomations. 12 At the experimental level, it has been shown that chelating agents, such as EDTA salts, as well as Batimastat, are effective at inhibiting both the isolated SVMPs and the hemorrhagic activity of crude viperid venoms in animal models, 13,14 underscoring the potential therapeutic value of such inhibitors in this pathology.…”

“…4−9 Most MMP inhibitors to date developed consist of a zinc-binding group (ZBG), which binds the catalytic metal ion, 5,8,10 and a peptidomimetic backbone, which interacts noncovalently with the active site of the enzyme. 7,11 The peptidomimetic Batimastat (BB-94) is a first generation MMP inhibitor that contains the most common ZBG, that is, a hydroxamate moiety.…”