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PDBsum entry 1m1v
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References listed in PDB file
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Key reference
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Title
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Modeling of enzyme-Substrate complexes for the metalloproteases mmp-3, Adam-9 and adam-10.
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Authors
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S.Manzetti,
D.R.Mcculloch,
A.C.Herington,
D.Van der spoel.
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Ref.
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J Comput Aided Mol Des, 2003,
17,
551-565.
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PubMed id
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Abstract
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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.
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