Structure-based pKa prediction provides a thermodynamic basis for the role of histidines in pH-induced conformational transitions in dengue virus

Chaudhury, Sidhartha; Ripoll, Daniel R.; Wallqvist, Anders

doi:10.1016/j.bbrep.2015.10.014

Cited by 16 publications

(16 citation statements)

References 35 publications

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“…Protein sequences were compared using the program Clustal Omega, and the conservation of the amino acids was visualized using the program Consurf 68 . Predictions of pKa were calculated using Rosetta-pKa 36 , according to the method described for DENV E-protein by Chaudhury et al 69 . Electrostatic surfaces were visualized in the program PyMOL using the APBS and PDB2PQR plugins.…”

Section: Methodsmentioning

confidence: 99%

Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

et al. 2018

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Tick-borne encephalitis virus (TBEV) causes 13,000 cases of human meningitis and encephalitis annually. However, the structure of the TBEV virion and its interactions with antibodies are unknown. Here, we present cryo-EM structures of the native TBEV virion and its complex with Fab fragments of neutralizing antibody 19/1786. Flavivirus genome delivery depends on membrane fusion that is triggered at low pH. The virion structure indicates that the repulsive interactions of histidine side chains, which become protonated at low pH, may contribute to the disruption of heterotetramers of the TBEV envelope and membrane proteins and induce detachment of the envelope protein ectodomains from the virus membrane. The Fab fragments bind to 120 out of the 180 envelope glycoproteins of the TBEV virion. Unlike most of the previously studied flavivirus-neutralizing antibodies, the Fab fragments do not lock the E-proteins in the native-like arrangement, but interfere with the process of virusinduced membrane fusion.

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Section: Methodsmentioning

confidence: 99%

Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

et al. 2018

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“…Residues were marked as (i) completely conserved, (ii) stereochemically equivalent or (iii) not conversed. His317, the residue implicated in pH sensing 66 , 67 , switches electrostatic polarity with respect to Thr315 ( Table 1 ). Both His317 and Thr315 are conserved in ZIKV/DENV1-4/JEV/WNV ( Figure 2 ), and are known epitopes 23 , 43 .…”

Section: Resultsmentioning

confidence: 99%

Computational analysis of perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus

Chakraborty¹

2016

F1000Res

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The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV) in three countries, provides key insights in developing strategies for tackling ZIKV, which has caused global panic to microcephaly and Guillain-Barre Syndrome. Dengue virus (DENV), a member of the family , the causal agent of the self-limiting Dengue fever and the Flaviviridae potentially fatal hemorrhagic fever/dengue shock syndrome, has been a scourge in tropical countries for many centuries. The recently solved structure of mature ZIKV (PDB ID:5IRE) has provided key insights into the structure of the envelope (E) and membrane (M) proteins, the primary target of neutralizing antibodies. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with significant spatial and electrostatic perturbations. In the current work, MEPP analyzed the pre-and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes (His317, Tyr299, Glu26, Arg188, etc.) (MEPPitope). These residues are overwhelmingly conserved in ZIKV and all DENV serotypes, and also enumerates residue pairs that undergo significant polarity reversal. Characterization of α-helices in E-proteins show that α1 is not conserved in the sequence space of ZIKV and DENV. Furthermore, perturbation of α1 in the post-fusion DENV structure includes a known epitope Asp215, a residue absent in the pre-fusion α1. A cationic β-sheet in the GAG-binding domain that is stereochemically equivalent in ZIKV and all DENV serotypes is also highlighted due to a residue pair (Arg286-Arg288) that has a significant electrostatic polarity reversal upon fusion. Finally, two highly conserved residues (Thr32 and Thr40), with little emphasis in existing literature, are found to have significant electrostatic perturbation. Thus, a combination of different computational methods enable the rapid and rational detection of critical residues as epitopes in the search for an elusive therapy or vaccine that neutralizes multiple members of the family. These secondary Flaviviridae structures are conserved in the related Dengue virus (DENV), and possibly rationalize isolation techniques particle adsorption on magnetic beads coated No competing interests were disclosed. Competing interests:The author(s) declared that no grants were involved in supporting this work. Amendments from Version 1The revised manuscript incorporates minor suggestions from the reviewers: a) Title has been changed b) Helices 5 and 6 now labelled in Figure 1. c) References to recent work on antibodies cited (79 and 88).

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“…It remains unclear how the R843H variant affects MDA5 function, but mutations near ATP binding and phosphorylation sites may alter viral sensing and IFN-α/β synthesis. Arginine is a strongly charged amino acid with a pKa 3 of ≈13.8 at physiological pH and has a robust role in protein structure and folding [235]; whereas, histidine has a lower positive charge than arginine with a pKa 3 ≈6.3 [236]. Charged residues are typically located in functional regions of proteins.…”

Section: T1d Risk-associated Snps In Ifih1mentioning

confidence: 99%

Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

Blum¹,

Tse²

2020

Microorganisms

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Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing β-cells. The concordance rate for T1D in monozygotic twins is ≈30–50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/β). Viral infection and subsequent IFN-α/β synthesis can lead to ER stress within insulin-producing β-cells causing neo-epitope generation, activation of β-cell-specific autoreactive T cells, and β-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.

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Structure-based pKa prediction provides a thermodynamic basis for the role of histidines in pH-induced conformational transitions in dengue virus

Cited by 16 publications

References 35 publications

Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

Structure of tick-borne encephalitis virus and its neutralization by a monoclonal antibody

Computational analysis of perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus

Innate Viral Sensor MDA5 and Coxsackievirus Interplay in Type 1 Diabetes Development

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