Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10
- Cite this article as:
- Manzetti, S., McCulloch, D.R., Herington, A.C. et al. J Comput Aided Mol Des (2003) 17: 551. doi:10.1023/B:JCAM.0000005765.13637.38
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The matrix metalloproteases (MMPs) and the ADAMs (A Disintegrin And Metalloprotease domain) are proteolytic enzyme families containing a catalytic zinc ion, that are implicated in a variety of normal and pathological processes involving tissue remodeling and cancer. Synthetic MMP inhibitors have been designed for applications in pathological situations. However, a greater understanding of substrate binding and the catalytic mechanism is required so that more effective and selective inhibitors may be developed for both experimental and clinical purposes. By modeling a natural substrate spanning P4-P4′ in complex with the catalytic domains, we aim to compare substrate-specificities between Stromelysin-1 (MMP-3), ADAM-9 and ADAM–10, with the aid of molecular dynamics simulations. Our results show that the substrate retains a favourable antiparallel beta-sheet conformation on the P-side in addition to the well-known orientation of the P′-region of the scissile bond, and that the primary substrate selectivity is dominated by the sidechains in the S1′ pocket and the S2/S3 region. ADAM-9 has a hydrophobic residue as the central determinant in the S1′ pocket, while ADAM-10 has an amphiphilic residue, which suggests a different primary specificity. The S2/S3 pocket is largely hydrophobic in all three enzymes. Inspired by our molecular dynamics calculations and supported by a large body of literature, we propose a novel, hypothetical, catalytic mechanism where the Zn-ion polarizes the oxygens from the catalytic glutamate to form a nucleophile, leading to a tetrahedral oxyanion anhydride transition state.