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- PDB-8dv6: Zika virus envelope protein structure in complex with a potent Hu... -

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Basic information

Entry
Database: PDB / ID: 8dv6
TitleZika virus envelope protein structure in complex with a potent Human mAb
Components
  • Envelope protein E
  • mAb Fab Heavy Chain
  • mAb Fab Light Chain
KeywordsVIRAL PROTEIN / Zika virus / envelope protein / neutralizing antibody / neutralization mechanism / flavivirus / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / host cell endoplasmic reticulum membrane / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / host cell endoplasmic reticulum membrane / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont entry into host cell / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / virion attachment to host cell / virion membrane / structural molecule activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase ...Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesZika virus ZIKV/Human/Cambodia/FSS13025/2010
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.38 Å
AuthorsCameron, A. / Puhl, A.C. / deSilva, A.M. / Premkumar, L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)BAA 2017-N-18041 United States
CitationJournal: PLoS Pathog / Year: 2023
Title: Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.
Authors: Cameron Adams / Derek L Carbaugh / Bo Shu / Thiam-Seng Ng / Izabella N Castillo / Ryan Bhowmik / Bruno Segovia-Chumbez / Ana C Puhl / Stephen Graham / Sean A Diehl / Helen M Lazear / Shee- ...Authors: Cameron Adams / Derek L Carbaugh / Bo Shu / Thiam-Seng Ng / Izabella N Castillo / Ryan Bhowmik / Bruno Segovia-Chumbez / Ana C Puhl / Stephen Graham / Sean A Diehl / Helen M Lazear / Shee-Mei Lok / Aravinda M de Silva / Lakshmanane Premkumar /
Abstract: We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing ...We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency.
History
DepositionJul 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 4, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Refinement description / Category: citation / citation_author / struct_ncs_dom_lim
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Envelope protein E
B: Envelope protein E
C: mAb Fab Heavy Chain
D: mAb Fab Light Chain
H: mAb Fab Heavy Chain
L: mAb Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)188,4596
Polymers188,4596
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)95.041, 133.609, 105.109
Angle α, β, γ (deg.)90.000, 106.494, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
12
22
13
23

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111ILEILEPHEPHE(chain 'A' and (resid 1 through 184 or resid 186 through 405))AA1 - 1831 - 183
121LEULEUGLYGLY(chain 'A' and (resid 1 through 184 or resid 186 through 405))AA186 - 404186 - 404
211ILEILEPHEPHE(chain 'B' and (resid 1 through 184 or resid 186 through 405))BB1 - 1831 - 183
221LEULEUGLYGLY(chain 'B' and (resid 1 through 184 or resid 186 through 405))BB186 - 404186 - 404
132ARGARGLYSLYS(chain 'C' and resid 1 through 230)CC1 - 2291 - 229
232ARGARGLYSLYSchain 'H'HE1 - 2291 - 229
133SERSERPROPROchain 'D'DD2 - 2122 - 212
233SERSERPROPROchain 'L'LF2 - 2122 - 212

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Envelope protein E /


Mass: 45331.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus ZIKV/Human/Cambodia/FSS13025/2010
Production host: Homo sapiens (human) / References: UniProt: A0A384KMW4
#2: Antibody mAb Fab Heavy Chain


Mass: 25868.793 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody mAb Fab Light Chain


Mass: 23029.385 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.4 Å3/Da / Density % sol: 63.78 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: PEG8000, HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Nov 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.38→50 Å / Num. obs: 35195 / % possible obs: 99.4 % / Redundancy: 7.5 % / Biso Wilson estimate: 95.67 Å2 / Rmerge(I) obs: 0.177 / Rpim(I) all: 0.07 / Net I/σ(I): 12.9
Reflection shellResolution: 3.38→3.46 Å / Redundancy: 7 % / Rmerge(I) obs: 1.434 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1718 / CC1/2: 0.62 / CC star: 0.876 / Rpim(I) all: 0.585 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JHM

5jhm


Resolution: 3.38→45.57 Å / SU ML: 0.4329 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.7627
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.2586 1689 4.8 %Random
Rwork0.2323 33478 --
obs0.2336 35167 99.45 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 120.67 Å2
Refinement stepCycle: LAST / Resolution: 3.38→45.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12826 0 0 0 12826
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002313136
X-RAY DIFFRACTIONf_angle_d0.618517856
X-RAY DIFFRACTIONf_chiral_restr0.04421993
X-RAY DIFFRACTIONf_plane_restr0.0042299
X-RAY DIFFRACTIONf_dihedral_angle_d5.16181815
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.38-3.480.35581390.34682610X-RAY DIFFRACTION93.66
3.48-3.590.31461530.32172770X-RAY DIFFRACTION99.93
3.59-3.720.39861250.33082827X-RAY DIFFRACTION99.9
3.72-3.870.36111530.30522774X-RAY DIFFRACTION100
3.87-4.040.2851290.27442804X-RAY DIFFRACTION100
4.04-4.260.29351330.25532782X-RAY DIFFRACTION100
4.26-4.520.25171460.22622823X-RAY DIFFRACTION100
4.52-4.870.21291510.20062779X-RAY DIFFRACTION100
4.87-5.360.23071370.20312792X-RAY DIFFRACTION99.97
5.36-6.140.24211470.21782807X-RAY DIFFRACTION100
6.14-7.730.25251290.22532844X-RAY DIFFRACTION100
7.73-45.570.20641470.17732866X-RAY DIFFRACTION99.9
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.733171963892.30486382688-3.023789762673.29260849396-3.148964271143.94437668803-0.01060953918370.41036277360.119253545245-0.2604640137720.335763876089-0.06526019096230.0669434583229-0.169976484348-0.2881473057680.580029434489-0.076339771314-0.1508057103860.811447542518-0.2053394932210.687110705145-75.404-20.03135.704
21.078617224040.517500416923-0.7180788700612.86205937596-2.146642744763.760730707880.0395502121294-0.7242988012260.1702001879911.206597513520.0980445959232-0.0100547821586-0.142507340675-0.0979864338789-0.1003779366771.232401003830.159562326213-0.0652531524841.144837625-0.1828750905450.742125458236-96.023-32.39585.408
34.59476387231.415830376591.623876274170.9016357688510.8254390833232.25064747725-0.07471906033891.61757701274-1.1606342299-0.2748260971440.166871860202-0.195842231610.4715499204630.245297661492-0.1137167375670.8858142662080.01066112361310.2330163203511.19559183364-0.5721895126851.43056642204-109.243-21.40520.276
45.544021876110.434356175475-0.4883230099411.64980988014-0.2983646899321.179636388420.06546647841510.3570963783491.591314877990.122183522486-0.01072089597940.857928374771-0.113058093784-0.491753702005-0.06439657018440.50886138880.0123899641631-0.05905315577280.621187891477-0.01597462319031.22105982-137.174-35.7357.128
57.42030974242-0.6168573046490.4968275591840.319221913346-0.6665935740760.878220802735-0.278508620806-1.260416713341.321384780530.3917747775810.1712251682240.345453678081-0.392004467171-0.3071165541650.1027526843550.7225448291520.055480246774-0.06974930349470.85662956863-0.3432078231011.08669841538-129.588-31.0373.015
63.59870320329-0.2040353607080.2987544066461.334527172770.7638288785891.97232333974-0.1492301417910.852301424617-0.917319557437-0.374361122735-0.24884595520.1195350911040.282814335548-0.4813701017880.2608018005930.800201900979-0.09386858275650.133191801940.779182432128-0.4304099251131.0514892084-125.392-16.33226.506
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 1:405 )A1 - 405
2X-RAY DIFFRACTION2( CHAIN B AND RESID 1:405 )B1 - 405
3X-RAY DIFFRACTION3( CHAIN C AND RESID 1:231 )C1 - 231
4X-RAY DIFFRACTION4( CHAIN D AND RESID 2:213 )D2 - 213
5X-RAY DIFFRACTION5( CHAIN H AND RESID 1:229 )H1 - 229
6X-RAY DIFFRACTION6( CHAIN L AND RESID 2:213 )L2 - 213

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