Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections
Abstract
:1. Introduction
2. Materials and Methods
2.1. Expression and Purification of ADI-30056 and ADI-30056 Fab for Biochemical Assays
2.2. Generation of ZIKV and DENV for Biochemical Assays
2.3. Focus Reduction Neutralization Test (FRNT)
2.4. Enzyme-Linked ImmunoSorbent Assay (ELISA)
2.5. Shotgun Mutagenesis Epitope Mapping
2.6. Cryo-EM Reconstruction and Structure Refinement of ZIKV-ADI-Fab30056 Complex
2.7. Multiple Sequence Alignment, 3D Superposition, Residue Contact Analysis and Calculation of Surface Properties
2.8. Data Availability
3. Results
3.1. Structure of ZIKV in Complex with ADI-Fab30056
3.2. ADI-Fab30056 Interactions with ZIKV and ZIKV Specific Neutralization
4. Discussion
4.1. Evolution of Potent ZIKV-Specific Antibodies
4.2. Translational Applicability of ADI-30056 for Ab-Based Therapeutics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Data Statistics | |
---|---|
Microscope | FEI Titan Krios |
Magnification (×) | 81,000 |
Voltage (kV) | 300 |
Detector | Gatan K2 Summit |
Micrograph collection mode | Super-resolution |
Total dose (e-/Å2) | 30 |
Defocus range (m) | 1.0–2.5 |
Pixel size (Å) | 0.86 |
Symmetry imposed | Icosahedral |
Map resolution (FSC 0.143; Å) | 4.0 |
Map sharpening B-factor (Å2) | −200.86 |
Refinement statistics | |
Real-space correlation coefficient | 0.8 |
Root-mean-square deviation (r.m.s.d.) bond lengths (Å) | 0.02 |
r.m.s.d bond angles in degrees (º) | 1.25 |
Clash score | 13 |
Poor rotamers (%) | 4.5% |
Ramachandran plot | |
Favored (%) | 88.4 |
Allowed (%) | 11.6 |
Outliers (%) | 0.0 |
E5 | Fab Heavy (H) or Light (L) Chains | Distance (Å) |
---|---|---|
Asp83 (b-c loop) | H:Y59 (VH-CDR2) | 2.86 |
Ser 86 (b-c loop) | H:Y59 (VH-CDR2) | 3.55 |
Asp87 (b-c loop) | H:R52 (VH-CDR2) | 2.66 (salt bridge) |
Thr88 (b-c loop) | H:R52 (VH-CDR2) | 3.28 |
Gln89 (b-c loop) ** | H:E101 (VH-CDR3) | 2.94 |
Lys118 (strand-d) ** | H:E101 (VH-CDR3) | 3.46 (salt bridge) |
Lys124 (d-e loop) | H:R52 (VH-CDR2) | 2.88 |
Lys124 (d-e loop) | H:E102 (VH-CDR3) | 2.88 (salt bridge) |
Thr231 (h-i loop) | H:N31 (VH-CDR1) | 2.77 |
Asp67 (strand-b) ** | L:S91 (VL-CDR3) | 2.71 |
Asp67 (strand-b) | L:R96 (VL-CDR3) | 3.61 (salt bridge) |
Met68 (strand-b) | L:S94 (VL-CDR3) | 3.39 |
Met68 (strand-b) | L:Y92 (VL-CDR3) | 2.75 |
Lys84 (b-c loop) | L:S94 (VL-CDR3) | 2.53 |
Val255 (i-j loop) | L:Y92 (VL-CDR3) | 3.78 |
E2 | Fab Heavy (H) or Light (L) chains | Distance (Å) |
Tyr81 (b-c loop) | H:Y53 (VH-CDR2) | 3.76 |
Asp83 (b-c loop) | H:R30 (VH-CDR1) | 2.40 (salt bridge) |
Ser86 (b-c loop) | H:Y53 (VH-CDR2) | 2.27 |
Ser86 (b-c loop) | H:R52 (VH-CDR2) | 2.75 |
E3 | Fab Heavy (H) or Light (L) chains | Distance (Å) |
Asn208 (f-g loop) | L:T31 (VL-CDR1) | 3.38 |
Asn208 (f-g loop) | L:S67 (VL-FR3) | 3.59 |
Glu276 (strand-K) | L:S28 (VL-CDR1) | 3.45 |
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Sevvana, M.; Rogers, T.F.; Miller, A.S.; Long, F.; Klose, T.; Beutler, N.; Lai, Y.-C.; Parren, M.; Walker, L.M.; Buda, G.; et al. Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections. Viruses 2020, 12, 1346. https://doi.org/10.3390/v12121346
Sevvana M, Rogers TF, Miller AS, Long F, Klose T, Beutler N, Lai Y-C, Parren M, Walker LM, Buda G, et al. Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections. Viruses. 2020; 12(12):1346. https://doi.org/10.3390/v12121346
Chicago/Turabian StyleSevvana, Madhumati, Thomas F. Rogers, Andrew S. Miller, Feng Long, Thomas Klose, Nathan Beutler, Yen-Chung Lai, Mara Parren, Laura M. Walker, Geeta Buda, and et al. 2020. "Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections" Viruses 12, no. 12: 1346. https://doi.org/10.3390/v12121346