Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10

Manzetti, Sergio, McCulloch, Daniel R., Herington, Adrian C. and van der Spoel, David 2003, Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10, Journal of computer aided molecular design, vol. 17, no. 9, pp. 551-565, doi: 10.1023/B:JCAM.0000005765.13637.38.

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Title Modeling of enzyme–substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10
Author(s) Manzetti, Sergio
McCulloch, Daniel R.
Herington, Adrian C.
van der Spoel, David
Journal name Journal of computer aided molecular design
Volume number 17
Issue number 9
Start page 551
End page 565
Publisher Springer Netherlands
Place of publication Dordrecht , The Netherlands
Publication date 2003-09
ISSN 0920-654X
Keyword(s) ADAM (A Disintegrin And Metalloprotease domain)
catalytic mechanism
matrix metalloproteases (MMPs)
substrate specificity
Summary 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.
Language eng
DOI 10.1023/B:JCAM.0000005765.13637.38
Field of Research 030402 Biomolecular Modelling and Design
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Kluwer Academic Publishers
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Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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