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Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Targets

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Identification of Alternative Allosteric Sites in Glycolytic Enzymes for Potential Use as Species-Specific Drug Target.pdf (7.179Mb)
Date
2020
Author
Ayyıldız, Merve
Çeliker, Serkan
Özhelvacı, Fatih
Akten, Ebru Demet
Abstract
Three allosteric glycolytic enzymes, phosphofructokinase, glyceraldehyde-3 phosphate dehydrogenase and pyruvate kinase, associated with bacterial, parasitic and human species, were explored to identify potential allosteric sites that would be used as prime targets for species-specific drug design purposes using a newly developed approach which incorporates solvent mapping, elastic network modeling, sequence and structural alignments. The majority of binding sites detected by solvent mapping overlapped with the interface regions connecting the subunits, thus appeared as promising target sites for allosteric regulation. Each binding site was then evaluated by its ability to alter the global dynamics of the receptor defined by the percentage change in the frequencies of the lowest-frequency modes most significantly and as anticipated, the most effective ones were detected in the vicinity of the well-reported catalytic and allosteric sites. Furthermore, some of our proposed regions intersected with experimentally resolved sites which are known to be critical for activity regulation, which further validated our approach. Despite the high degree of structural conservation encountered between bacterial/parasitic and human glycolytic enzymes, the majority of the newly presented allosteric sites exhibited a low degree of sequence conservation which further increased their likelihood to be used as species-specific target regions for drug design studies.

Source

Frontiers in Molecular Biosciences

Volume

7

URI

https://doi.org/10.3389/fmolb.2020.00088
https://hdl.handle.net/20.500.12469/2924

Collections

  • Araştırma Çıktıları / PubMed [187]
  • Araştırma Çıktıları / Scopus [1319]
  • Araştırma Çıktıları / WOS [1335]
  • Biyoinformatik ve Genetik / Bioinformatics and Genetics [212]

Keywords

Allosteric regulation
Glycolytic enzyme
Elastic network modeling
Species-specific
Drug discovery

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