Structural Analysis of Rabies Virus Glycoprotein Reveals pH-Dependent Conformational Changes and Interactions with a Neutralizing Antibody

Yang, Fulun; Lin, Sheng; Ye, Fei; Yang, Jing; Qi, Jianxun; Chen, Zhujun; Lin, Xi; Wang, Jichao; Yue, Dan; Cheng, Yanwei; Chen, Zimin; Chen, Hua; Yu, You; Zhang, Zhonglin; Yu, Yang; Yang, Ming; Sun, Honglu; Li, Yuhua; Cao, Yu; Yang, Shengyong; Wei, Yuquan; Gao, George F.; Lu, Guangwen

doi:10.1016/j.chom.2019.12.012

Cited by 68 publications

(107 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite belonging to evolutionary seemingly unrelated virus families, the arrangement and structure of their individual domains are conserved (Fig. 1, A and B), but high-resolution structures for the prefusion form are only available for two rhabdovirus glycoproteins (12,13). In the postfusion conformation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The prefusion structure of herpes simplex virus glycoprotein B

et al. 2020

View full text Add to dashboard Cite

Cell entry of enveloped viruses requires specialized viral proteins that mediate fusion with the host membrane by substantial structural rearrangements from a metastable pre- to a stable postfusion conformation. This metastability renders the herpes simplex virus 1 (HSV-1) fusion glycoprotein B (gB) highly unstable such that it readily converts into the postfusion form, thereby precluding structural elucidation of the pharmacologically relevant prefusion conformation. By identification of conserved sequence signatures and molecular dynamics simulations, we devised a mutation that stabilized this form. Functionally locking gB allowed the structural determination of its membrane-embedded prefusion conformation at sub-nanometer resolution and enabled the unambiguous fit of all ectodomains. The resulting pseudo-atomic model reveals a notable conservation of conformational domain rearrangements during fusion between HSV-1 gB and the vesicular stomatitis virus glycoprotein G, despite their very distant phylogeny. In combination with our comparative sequence-structure analysis, these findings suggest common fusogenic domain rearrangements in all class III viral fusion proteins.

show abstract

Section: Resultsmentioning

confidence: 99%

The prefusion structure of herpes simplex virus glycoprotein B

et al. 2020

View full text Add to dashboard Cite

show abstract

“…There is structural evidence supporting the hypothesis that SARS-CoV-2 virus is a nicotinic agent. The recently reported X-ray structure of the RABV glycoprotein (G) ectodomain [49] shows that the region corresponding to the neurotoxin-like peptide is exposed at the G surface, in agreement with the fact that this region is part of the major antigenic region II of RABV [50]. The recently published cryo-EM structure of the trimeric SARS-CoV-2 spike (S) protein [51,52] revealed an insertion with respect to that of SARS-CoV-1, in a loop that is disordered in the reported structure, and which has a polybasic sequence that corresponds to a furin site.…”

mentioning

confidence: 99%

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Changeux¹,

Amoura²,

Rey³

et al. 2020

Comptes Rendus. Biologies

222

127

View full text Add to dashboard Cite

Background: Ivermectin is a widely used antiparasitic drug with known e cacy against several single-strain RNA viruses. Recent data shows signi cant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. Methods: An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology pro le including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic pro le of ivermectin in plasma and lungs was determined in all animals. Results: There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 grams/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean C max 86.2 ng/ml vs 26.2 ng/ml in the lower dose group and 152 ng/ml vs 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for lowdose females. Conclusion: nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

show abstract

“…Recent studies have confirmed the crystal structures of RABV G and its interaction with neutralizing antibodies (Hellert et al, 2020;Yang et al, 2020). Residues from G333-G350 of ectodomain from three strains (CVS-11, Flury, and SAD-B19) are observed to bond to antibody 523-11 (Yang et al, 2020).…”

Section: Figure 5 | (A)mentioning

confidence: 77%

Amino Acid Mutation in Position 349 of Glycoprotein Affect the Pathogenicity of Rabies Virus

Luo

Zhang

et al. 2020

Front. Microbiol.

View full text Add to dashboard Cite

Rabies, caused by rabies virus (RABV), is a zoonotic disease infecting mammals including humans. Studies have confirmed that glycoprotein (G) is most related to RABV pathogenicity. In the present study, to discover more amino acid sites related to viral pathogenicity, artificial mutants have been constructed in G of virulent strain GD-SH-01 backbone. Results showed that pathogenicity of GD-SH-01 significantly decreased when Gly 349 was replaced by Glu 349 through in vivo assays. Gly 349 →Glu 349 of G did not significantly influence viral growth and spread in NA cells. Gly 349 →Glu 349 of G increased the immunogenicity of GD-SH-01 in periphery and induced more expression of interferon alpha (IFN-α) in the brain in mice. It was observed that Gly 349 →Glu 349 of G led to enhanced blood-brain barrier (BBB) permeability at day 5 postinfection. All together, these data revealed that Gly 349 →Glu 349 of G mutation decreased RABV pathogenicity through enhanced immune response and increased BBB permeability. This study provides a new referenced site G349 that could attenuate pathogenicity of RABV.

show abstract

Structural Analysis of Rabies Virus Glycoprotein Reveals pH-Dependent Conformational Changes and Interactions with a Neutralizing Antibody

Cited by 68 publications

References 62 publications

The prefusion structure of herpes simplex virus glycoprotein B

The prefusion structure of herpes simplex virus glycoprotein B

A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

Amino Acid Mutation in Position 349 of Glycoprotein Affect the Pathogenicity of Rabies Virus

Contact Info

Product

Resources

About