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- PDB-8kg5: Prefusion RSV F Bound to Lonafarnib and D25 Fab -

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Basic information

Entry
Database: PDB / ID: 8kg5
TitlePrefusion RSV F Bound to Lonafarnib and D25 Fab
Components
  • D25 heavy chain
  • D25 light chain
  • Fusion glycoprotein F0,Fibritin
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Respiratory syncytial virus / F protein / Lonafarnib / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


positive regulation of syncytium formation by virus / Translation of respiratory syncytial virus mRNAs / RSV-host interactions / Maturation of hRSV A proteins / Assembly and release of respiratory syncytial virus (RSV) virions / host cell Golgi membrane / Respiratory syncytial virus (RSV) attachment and entry / virion component / entry receptor-mediated virion attachment to host cell / symbiont entry into host cell ...positive regulation of syncytium formation by virus / Translation of respiratory syncytial virus mRNAs / RSV-host interactions / Maturation of hRSV A proteins / Assembly and release of respiratory syncytial virus (RSV) virions / host cell Golgi membrane / Respiratory syncytial virus (RSV) attachment and entry / virion component / entry receptor-mediated virion attachment to host cell / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / identical protein binding / plasma membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / Fibritin C-terminal / Fibritin C-terminal region
Similarity search - Domain/homology
Chem-336 / Fusion glycoprotein F0 / Fibritin
Similarity search - Component
Biological speciesHuman respiratory syncytial virus A
Enterobacteria phage T4 (virus)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.17 Å
AuthorsYang, Q. / Xue, B. / Liu, F. / Peng, W. / Chen, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32000111 China
CitationJournal: Signal Transduct Target Ther / Year: 2024
Title: Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
Authors: Qi Yang / Bao Xue / Fengjiang Liu / Yongzhi Lu / Jielin Tang / Mengrong Yan / Qiong Wu / Ruyi Chen / Anqi Zhou / Lijie Liu / Junjun Liu / Changbin Qu / Qingxin Wu / Muqing Fu / Jiayi Zhong / ...Authors: Qi Yang / Bao Xue / Fengjiang Liu / Yongzhi Lu / Jielin Tang / Mengrong Yan / Qiong Wu / Ruyi Chen / Anqi Zhou / Lijie Liu / Junjun Liu / Changbin Qu / Qingxin Wu / Muqing Fu / Jiayi Zhong / Jianwei Dong / Sijie Chen / Fan Wang / Yuan Zhou / Jie Zheng / Wei Peng / Jinsai Shang / Xinwen Chen /
Abstract: Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules ...Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.
History
DepositionAug 17, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fusion glycoprotein F0,Fibritin
B: Fusion glycoprotein F0,Fibritin
C: Fusion glycoprotein F0,Fibritin
D: D25 heavy chain
E: D25 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)243,3398
Polymers241,4225
Non-polymers1,9163
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Fusion glycoprotein F0,Fibritin / Collar protein / Whisker antigen control protein


Mass: 64530.602 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human respiratory syncytial virus A (strain A2), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: F, wac / Production host: Homo sapiens (human) / References: UniProt: P03420, UniProt: P10104
#2: Antibody D25 heavy chain


Mass: 24504.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody D25 light chain


Mass: 23325.865 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-336 / 4-{2-[4-(3,10-DIBROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDIN-11-YL)PIPERIDIN-1-YL]-2-OXOETHYL}PIPERIDINE-1-CARBOXAMIDE / SCH66336


Mass: 638.822 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H31Br2ClN4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Prefusion RSV F Bound to Lonafarnib and D25 Fab / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Human respiratory syncytial virus A (strain A2)11259
31Enterobacteria phage T4 (virus)10665
41Homo sapiens (human)9606
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.17 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 37059 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00712407
ELECTRON MICROSCOPYf_angle_d0.91416824
ELECTRON MICROSCOPYf_dihedral_angle_d16.7037544
ELECTRON MICROSCOPYf_chiral_restr0.0542011
ELECTRON MICROSCOPYf_plane_restr0.0052120

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