An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole
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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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American Chemical Society (ACS)
2020
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| Online Access: | https://hdl.handle.net/1721.1/125571 |
| _version_ | 1826200305705943040 |
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| author | Windsor, Ian William Gold, Brian Raines, Ronald T |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Windsor, Ian William Gold, Brian Raines, Ronald T |
| author_sort | Windsor, Ian William |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:34:26Z |
| format | Article |
| id | mit-1721.1/125571 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:34:26Z |
| publishDate | 2020 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1255712022-10-01T04:31:19Z An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole Windsor, Ian William Gold, Brian Raines, Ronald T Massachusetts Institute of Technology. Department of Chemistry 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. National Institutes of Health (U.S.) (Grant S10 OD023532) National Institutes of Health (U.S.) (Grant R01 GM044783) 2020-05-29T13:05:39Z 2020-05-29T13:05:39Z 2019-02 2020-01-07T15:01:04Z Article http://purl.org/eprint/type/JournalArticle 1944-8252 1944-8244 https://hdl.handle.net/1721.1/125571 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) en https://dx.doi.org/10.1021/ACSCATAL.8B04142 ACS Catalysis 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. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | Windsor, Ian William Gold, Brian Raines, Ronald T An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title | An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title_full | An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title_fullStr | An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title_full_unstemmed | An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title_short | An n →π* Interaction in the Bound Substrate of Aspartic Proteases Replicates the Oxyanion Hole |
| title_sort | n π interaction in the bound substrate of aspartic proteases replicates the oxyanion hole |
| url | https://hdl.handle.net/1721.1/125571 |
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