An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole
Name
nihms-1021080.pdf
Description
Accepted version
Size
1.46 MB
Format
Adobe PDF
Checksum (MD5)
25f0efc76fda52346fae0394c71af831
Author(s)
Windsor, Ian William
Gold, Brian
Raines, Ronald T
Date Issued
February 2019
Journal
ACS Catalysis
Publisher
American Chemical Society (ACS)
Citation
Windsor, Ian W. et al. “An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole.” ACS Catalysis 9 (2019): 1464-1471 © 2019 The Author(s)
Version
Author's final manuscript
Abstract
Aspartic proteases regulate many biological processes and are prominent targets for therapeutic intervention. Structural studies have captured intermediates along the reaction pathway, including the Michaelis complex and tetrahedral intermediate. Using a Ramachandran analysis of these structures, we discovered that residues occupying the P1 and P1′ positions (which flank the scissile peptide bond) adopt the dihedral angle of an inverse γ-turn and polyproline type-II helix, respectively. Computational analyses reveal that the polyproline type-II helix engenders an n→π∗ interaction in which the oxygen of the scissile peptide bond is the donor. This interaction stabilizes the negative charge that develops in the tetrahedral intermediate, much like the oxyanion hole of serine proteases. The inverse γ-turn serves to twist the scissile peptide bond, vacating the carbonyl π∗ orbital and facilitating its hydration. These previously unappreciated interactions entail a form of substrate-assisted catalysis and offer opportunities for drug design.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/ACSCATAL.8B04142
