DIRseq as a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences
- Department of Chemistry, University of Illinois Chicago, United States
- Department of Physics, University of Illinois Chicago, United States
Figures
Figure 1 with 1 supplement
Four intrinsically disordered proteins (IDPs) and drugs that bind to them.
(a) p27, p21, and SJ403. (b) p53 and epigallocatechin-3-gallate (EGCG). (c) α-Synuclein and Fasudil. For each IDP, the DIRseq propensities are rendered by a color spectrum from yellow for low values to red for high values. Predicted drug-interacting residues are shown with sidechains rendered in stick.
Figure 1—figure supplement 1
q parameters.
(a) Values in the original SeqDYN method (Qin and Zhou, 2024). (b) Modified values for DIRseq.
Figure 2 with 3 supplements
Comparison of DIRseq propensities with NMR chemical shift perturbations (CSPs).
(a) p27. (b) p21. (c) p53. (d) α-Synuclein. CSPs are displayed as blue bars and in units of ppb; CSP-identified drug-interacting residues are indicated by cyan shading. DIRseq predictions are shown as red curves. The ordinate scales are chosen so that the m+1.5 SD threshold for CSP is at the same height as the 50% threshold for DIRseq, indicated by a horizontal dashed line.
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Figure 2—source data 1
Source data for Figure 2.
- https://cdn.elifesciences.org/articles/107470/elife-107470-fig2-data1-v1.xlsx
Figure 2—figure supplement 1
Correlation between NMR chemical shift perturbation (CSP) and DIRseq propensity.
(a) p27. CSP data from Iconaru et al., 2015. (b) p21. CSP data from Iconaru et al., 2015. (c) p53. CSP data from Zhao et al., 2021. (d) α-Synuclein. CSP data from Robustelli et al., 2022.
Figure 2—figure supplement 2
Correlation of chemical shift perturbations (CSPs) elicited by two different compounds.
(a) α-Synuclein. Data from Robustelli et al., 2022. (b) Tau-5*. Data from Basu et al., 2023.
Figure 2—figure supplement 3
Two compounds that bind to p27 with different characteristics.
Figure 3
Drug-binding sites identified by combining chemical shift perturbation (CSP) or mutation data with DIRseq predictions.
(a) Tau-5*. (b) NS5A-D2D3. (c) β2 microglobulin. Display items in panels (a, b) have the same meanings as in Figure 2, except that cyan shading indicates consensus identification; in panel (c), vertical lines indicate mutation sites.
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Figure 3—source data 1
Source data for Figure 3.
- https://cdn.elifesciences.org/articles/107470/elife-107470-fig3-data1-v1.xlsx
Figure 4
Drug-binding sites identified by combining chemical shift perturbation (CSP) or mutation data with DIRseq predictions.
(a) hIAPP. (b) Aβ42. (c) c-Myc. Display items have the same meanings as in Figure 2, but with the following exceptions. (1) In panel (b), vertical lines indicate residues with prominent CSPs; those accompanied by NMR peak broadening have their vertical lines in dark color. (2) In panel (c), three CSP-identified drug-interacting regions are indicated by cyan, olive, and yellow shading. (3) The threshold for identifying drug-interacting residues is lowered to m+1.0 SD.
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Figure 4—source data 1
Source data for Figure 4.
- https://cdn.elifesciences.org/articles/107470/elife-107470-fig4-data1-v1.xlsx
Figure 5
Poses of p53-bound EGCG generated by docking.
Additional files
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Supplementary file 1
Supplementary tables.
- https://cdn.elifesciences.org/articles/107470/elife-107470-supp1-v1.docx
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MDAR checklist
- https://cdn.elifesciences.org/articles/107470/elife-107470-mdarchecklist1-v1.docx
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DIRseq as a method for predicting drug-interacting residues of intrinsically disordered proteins from sequences
eLife 14:RP107470.
https://doi.org/10.7554/eLife.107470.3
