Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu
Abstract
:1. Introduction
2. Results and Discussion
2.1. NS1 Structure’s Dynamics
2.2. Pocket Identification and Analysis
2.3. Characterization of Interactions between Influenza NS1 and Human PI3K or TRIM25
2.4. Binding of NS1 to PI3K and TRIM25 Is Mostly Driven by the Same Six Hotspot Residues
3. Materials and Methods
3.1. NS1 Three-Dimensional Protein Structures
3.2. Molecular Dynamics (MD) Protocol and Analysis
3.3. Molecular Dynamics Simulations of the NS1-PI3K and NS1-TRIM25 Complexes
3.4. Druggable Pockets Identification and Analysis
4. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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NS1 Residues | PI3K Residues |
---|---|
Ser 87 | His 450 |
Arg 88 | Met 568 |
Tyr 89 | Arg 571 |
Thr 91 | Lys 572 |
Met 93 | Arg 574 |
Leu 95 | Asp 575 |
Glu 96 | Gln 576 |
Glu 97 | Leu 578 |
Met 98 | Val 579 |
Ser 99 | Trp 580 |
Arg 100 | Thr 582 |
Asp 101 | Gln 583 |
Trp 102 | Lys 584 |
Cys 116 | Ala 586 |
Arg 118 | Arg 587 |
Asn 133 | Gln 588 |
Phe 134 | Lys 589 |
Ser 135 | Ile 591 |
Asn 133 | Asn 592 |
Phe 134 | Leu 595 |
Ser 135 | |
Glu 142 | |
Thr 143 | |
Leu 144 | |
Ile 145 | |
Leu 146 | |
Arg 148 | |
Glu 159 | |
Ser 161 | |
Pro 162 | |
Leu 163 | |
Pro 164 | |
Ser 165 |
NS1 Residues | TRIM25 |
---|---|
Ser 87 | Val 208 (chain N) |
Arg 88 | Ser 211 (chain N) |
Tyr 89 | Gln 212 (chain N) |
Leu 90 | Asn 214 (chain N) |
Thr 91 | Gly 215 (chain N) |
Met 93 | Arg 218 (chain N) |
Thr 94 | Ala 219 (chain N) |
Leu 95 | Asp 221 (chain N) |
Glu 96 | Asp 222 (chain N) |
Met 98 | Val 223 (chain N) |
Ser 99 | Asn 225 (chain N) |
Glu 101 | Arg 226 (chain N) |
Arg 118 | Asp 229 (chain N) |
Asn 133 | Met 232 (chain N) |
Ser 135 | Arg 236 (chain N) |
Ile 145 | Phe 274 (chain I) |
Leu 146 | Ile 277 (chain I) |
Arg 148 | Leu 281 (chain I) |
Glu 159 | Val 322 (chain I) |
Ser 161 | Tyr 323 (chain I) |
Pro 162 | Ile 324 (chain I) |
Pro 164 | Pro 325 (chain I) |
Glu 326 (chain I) | |
Val 327 (chain I) |
NS1 Residues | PI3K Residues | Residence Time Ratio |
---|---|---|
Tyr 89 | Met 568 | 1.00 |
Tyr 89 | Lys 572 | 1.00 |
Tyr 89 | Asp 575 | 1.00 |
Tyr 89 | Arg 571 | 1.00 |
Ser 135 | Lys 572 | 1.00 |
Ser 99 | Leu 578 | 1.00 |
Ser 99 | Ile 591 | 1.00 |
Met 98 | Leu 578 | 1.00 |
Met 98 | Asp 575 | 1.00 |
Leu 146 | Val 579 | 1.00 |
Leu 95 | Leu 595 | 1.00 |
Leu 95 | Leu 578 | 1.00 |
Leu 95 | His 450 | 1.00 |
Leu 95 | Arg 574 | 1.00 |
Ile 145 | Val 579 | 1.00 |
Ile 145 | Lys 572 | 1.00 |
Ile 145 | Gln 576 | 1.00 |
Ile 145 | Asp 575 | 1.00 |
Asn 133 | Asp 575 | 1.00 |
Thr 91 | Arg 571 | 0.99 |
Asp 101 | Gln 588 | 0.99 |
Ser 99 | Gln 588 | 0.98 |
Met 98 | Val 579 | 0.98 |
Leu 95 | Asp 575 | 0.98 |
Arg 148 | Thr 582 | 0.98 |
Ser 161 | Gln 583 | 0.97 |
Pro 162 | Gln 583 | 0.97 |
Arg 100 | Gln 588 | 0.97 |
Glu 142 | Lys 572 | 0.96 |
Thr 143 | Lys 572 | 0.95 |
Pro 162 | Val 579 | 0.95 |
Tyr 89 | Arg 574 | 0.94 |
Asp 101 | Arg 587 | 0.93 |
Thr 91 | Asp 575 | 0.92 |
Ser 161 | Val 579 | 0.92 |
Ser 87 | Lys 572 | 0.92 |
Thr 143 | Gln 576 | 0.90 |
Ser 99 | Leu 595 | 0.90 |
Glu 96 | Gln 588 | 0.87 |
Ser 99 | Thr 582 | 0.86 |
Arg 88 | Met 568 | 0.85 |
Met 98 | Thr 582 | 0.84 |
Asp 101 | Lys 589 | 0.82 |
Leu 163 | Gln 583 | 0.78 |
Tyr 89 | Gln 569 | 0.74 |
Leu 95 | Gln 588 | 0.73 |
Ser 99 | Asn 592 | 0.72 |
Asp 101 | Ala 586 | 0.72 |
NS1 Residues | TRIM25 Residues | Residence Time Ratio |
---|---|---|
Tyr 89 | Asp 229 | 1.00 |
Tyr 89 | Asp 222 | 1.00 |
Tyr 89 | Asn 225 | 1.00 |
Tyr 89 | Arg 226 | 1.00 |
Thr 94 | Arg 226 | 1.00 |
Thr 91 | Asp 222 | 1.00 |
Thr 91 | Arg 226 | 1.00 |
Ser 161 | Arg 218 | 1.00 |
Ser 99 | Ala 219 | 1.00 |
Pro 162 | Arg 218 | 1.00 |
Met 98 | Asp 222 | 1.00 |
Met 98 | Arg 226 | 1.00 |
Met 98 | Arg 218 | 1.00 |
Met 98 | Ala 219 | 1.00 |
Met 93 | Arg 226 | 1.00 |
Leu 146 | Arg 218 | 1.00 |
Leu 95 | Val 223 | 1.00 |
Leu 95 | Asp 222 | 1.00 |
Leu 95 | Arg 226 | 1.00 |
Ile 145 | Asp 222 | 1.00 |
Ile 145 | Asp 221 | 1.00 |
Ile 145 | Asn 225 | 1.00 |
Ile 145 | Arg 218 | 1.00 |
Glu 101 | Gln 212 | 1.00 |
Asn 133 | Asp 222 | 1.00 |
Asn 133 | Arg 226 | 1.00 |
Leu 146 | Gly 215 | 0.95 |
Ser 135 | Asn 225 | 0.94 |
Arg 88 | Asp 229 | 0.94 |
Met 98 | Gly 215 | 0.93 |
Arg 118 | Ser 211 | 0.93 |
Arg 148 | Gly 215 | 0.87 |
Leu 163 | Arg 218 | 0.84 |
Ser 99 | Ala 216 | 0.83 |
Ser 161 | Asn 214 | 0.82 |
Pro 164 | Arg 218 | 0.81 |
Arg 88 | Arg 236 | 0.75 |
Ser 87 | Met 232 | 0.74 |
Ile 145 | Ala 219 | 0.74 |
Leu 146 | Ala 219 | 0.71 |
NS1 Residues | TRIM25 Residues | Residence Time Ratio |
---|---|---|
Ser 99 | Leu 281 | 1.00 |
Ser 99 | Ile 324 | 1.00 |
Leu 95 | Pro 325 | 1.00 |
Leu 95 | Phe 274 | 1.00 |
Leu 95 | Ile 324 | 1.00 |
Leu 95 | Ile 277 | 1.00 |
Glu 96 | Ile 324 | 1.00 |
Leu 95 | Val 327 | 0.99 |
Ser 99 | Lys 284 | 0.97 |
Leu 95 | Leu 281 | 0.97 |
Leu 95 | Glu 326 | 0.94 |
Glu 101 | Lys 284 | 0.83 |
Glu 101 | Lys 320 | 0.78 |
Residues | Number of Pairwise Residue–Residue Interactions |
---|---|
Y89 | 6 |
L95 | 6 |
S99 | 6 |
M98 | 4 |
D101 | 4 |
I145 | 4 |
T91 | 2 |
T143 | 2 |
S161 | 2 |
P162 | 2 |
S87 | 1 |
R88 | 1 |
E96 | 1 |
R100 | 1 |
N133 | 1 |
S135 | 1 |
E142 | 1 |
L146 | 1 |
R148 | 1 |
L163 | 1 |
Residues | Number of Pairwise Residue–Residue Interactions |
---|---|
L95 | 10 |
M98 | 5 |
S99 | 5 |
I145 | 5 |
Y89 | 4 |
E101 | 3 |
L146 | 3 |
R88 | 2 |
T91 | 2 |
N133 | 2 |
S161 | 2 |
S87 | 1 |
M93 | 1 |
T94 | 1 |
E96 | 1 |
R118 | 1 |
S135 | 1 |
R148 | 1 |
P162 | 1 |
L163 | 1 |
P164 | 1 |
Residue NS1-ED | Residue PI3K-p85β | Residence Time (%) |
---|---|---|
P162 | Q583 | 26.97 |
Y89 | D575 | 76.22 |
N133 | D575 | 4.7 |
T91 | D575 | 0.3 |
S99 | Q588 | 1.9 |
S87 | K572 | 14.29 |
D101 | Q588 | 42.66 |
D101 | Q588 | 0.3 |
D101 | Q588 | 4.6 |
R118 | Q583 | 3.6 |
D101 | R587 | 20.78 |
P164 | W580 | 0.3 |
Y89 | R571 | 0.2 |
S165 | K584 | 0.2 |
S161 | Q583 | 1.3 |
S165 | S434 | 0.1 |
T143 | K572 | 0.9 |
S99 | N592 | 0.3 |
S161 | Q583 | 9.19 |
E96 | Q588 | 42.46 |
S99 | Q588 | 22.78 |
R88 | N561 | 1.4 |
T91 | R571 | 0.4 |
S87 | Q569 | 0.1 |
A86 | Q569 | 0.1 |
A86 | K572 | 0.1 |
W102 | R587 | 0.1 |
E159 | Q583 | 0.3 |
M98 | T582 | 0.9 |
E142 | K572 | 6.59 |
S135 | K572 | 1.5 |
Y89 | M568 | 2 |
M93 | R571 | 0.1 |
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Cunha, A.E.S.; Loureiro, R.J.S.; Simões, C.J.V.; Brito, R.M.M. Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu. Int. J. Mol. Sci. 2023, 24, 2977. https://doi.org/10.3390/ijms24032977
Cunha AES, Loureiro RJS, Simões CJV, Brito RMM. Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu. International Journal of Molecular Sciences. 2023; 24(3):2977. https://doi.org/10.3390/ijms24032977
Chicago/Turabian StyleCunha, Andreia E. S., Rui J. S. Loureiro, Carlos J. V. Simões, and Rui M. M. Brito. 2023. "Unveiling New Druggable Pockets in Influenza Non-Structural Protein 1: NS1–Host Interactions as Antiviral Targets for Flu" International Journal of Molecular Sciences 24, no. 3: 2977. https://doi.org/10.3390/ijms24032977