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- PDB-7t17: Zika Virus asymmetric unit bound with IgM antibody DH1017 Fab fragment -

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Basic information

Entry
Database: PDB / ID: 7t17
TitleZika Virus asymmetric unit bound with IgM antibody DH1017 Fab fragment
Components
  • Core proteinCapsid
  • DH1017.IgM FabC constant domain
  • DH1017.IgM IgH
  • DH1017.IgM IgL
  • DH1017.IgM LambdaC constant domain
KeywordsVIRUS / Zika Virus particle / IgM / Fab fragment / Neutralization
Function / homology
Function and homology information


positive regulation of B cell activation / phagocytosis, recognition / phagocytosis, engulfment / immunoglobulin complex / immunoglobulin complex, circulating / immunoglobulin receptor binding / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / complement activation, classical pathway / antigen binding / ribonucleoside triphosphate phosphatase activity ...positive regulation of B cell activation / phagocytosis, recognition / phagocytosis, engulfment / immunoglobulin complex / immunoglobulin complex, circulating / immunoglobulin receptor binding / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / complement activation, classical pathway / antigen binding / ribonucleoside triphosphate phosphatase activity / B cell receptor signaling pathway / viral capsid / double-stranded RNA binding / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / adaptive immune response / membrane => GO:0016020 / host cell endoplasmic reticulum membrane / protein dimerization activity / defense response to bacterium / symbiont entry into host cell / viral RNA genome replication / external side of plasma membrane / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / innate immune response / fusion of virus membrane with host endosome membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / virion membrane / proteolysis / extracellular exosome / extracellular region / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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 capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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. / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / 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 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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set 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 / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / Immunoglobulin-like fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Immunoglobulin lambda-like polypeptide 5 / Immunoglobulin gamma-1 heavy chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Zika virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.26 Å
AuthorsMiller, A.S. / Kuhn, R.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Cell / Year: 2022
Title: A Zika virus-specific IgM elicited in pregnancy exhibits ultrapotent neutralization.
Authors: Tulika Singh / Kwan-Ki Hwang / Andrew S Miller / Rebecca L Jones / Cesar A Lopez / Sarah J Dulson / Camila Giuberti / Morgan A Gladden / Itzayana Miller / Helen S Webster / Joshua A Eudailey ...Authors: Tulika Singh / Kwan-Ki Hwang / Andrew S Miller / Rebecca L Jones / Cesar A Lopez / Sarah J Dulson / Camila Giuberti / Morgan A Gladden / Itzayana Miller / Helen S Webster / Joshua A Eudailey / Kan Luo / Tarra Von Holle / Robert J Edwards / Sarah Valencia / Katherine E Burgomaster / Summer Zhang / Jesse F Mangold / Joshua J Tu / Maria Dennis / S Munir Alam / Lakshmanane Premkumar / Reynaldo Dietze / Theodore C Pierson / Eng Eong Ooi / Helen M Lazear / Richard J Kuhn / Sallie R Permar / Mattia Bonsignori /
Abstract: Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective ...Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.
History
DepositionDec 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 30, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI ..._citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: DH1017.IgM FabC constant domain
I: DH1017.IgM LambdaC constant domain
J: DH1017.IgM IgH
K: DH1017.IgM IgL
F: DH1017.IgM IgH
G: DH1017.IgM IgL
A: Core protein
C: Core protein
E: Core protein


Theoretical massNumber of molelcules
Total (without water)199,6799
Polymers199,6799
Non-polymers00
Water0
1
H: DH1017.IgM FabC constant domain
I: DH1017.IgM LambdaC constant domain
J: DH1017.IgM IgH
K: DH1017.IgM IgL
F: DH1017.IgM IgH
G: DH1017.IgM IgL
A: Core protein
C: Core protein
E: Core protein
x 60


Theoretical massNumber of molelcules
Total (without water)11,980,723540
Polymers11,980,723540
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
H: DH1017.IgM FabC constant domain
I: DH1017.IgM LambdaC constant domain
J: DH1017.IgM IgH
K: DH1017.IgM IgL
F: DH1017.IgM IgH
G: DH1017.IgM IgL
A: Core protein
C: Core protein
E: Core protein
x 5


  • icosahedral pentamer
  • 998 kDa, 45 polymers
Theoretical massNumber of molelcules
Total (without water)998,39445
Polymers998,39445
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
H: DH1017.IgM FabC constant domain
I: DH1017.IgM LambdaC constant domain
J: DH1017.IgM IgH
K: DH1017.IgM IgL
F: DH1017.IgM IgH
G: DH1017.IgM IgL
A: Core protein
C: Core protein
E: Core protein
x 6


  • icosahedral 23 hexamer
  • 1.2 MDa, 54 polymers
Theoretical massNumber of molelcules
Total (without water)1,198,07254
Polymers1,198,07254
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "C"
d_3ens_1chain "E"
d_1ens_2chain "J"
d_2ens_2chain "F"
d_1ens_3chain "K"
d_2ens_3chain "G"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1ILEGLYG1 - 392
d_21ens_1ILEGLYH1 - 392
d_31ens_1ILEGLYI1 - 392
d_11ens_2GLNSERC1 - 123
d_21ens_2GLNSERE1 - 123
d_11ens_3GLNLEUD1 - 110
d_21ens_3GLNLEUF1 - 110

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.964340253457, -0.0288667347268, 0.263086653383), (-0.0478943610277, -0.958589389728, -0.280735662293), (0.260295996404, -0.283325066888, 0.923023781237)176.314702016, 133.996804047, -4.40080795566
2given(0.966684636131, 0.0343891455488, 0.25364976037), (0.0357247820467, 0.963109905082, -0.266726546637), (-0.253465094668, 0.266902037088, 0.929795003419)30.8538379212, -17.3278419972, -8.62692750158
3given(-0.955749774342, 0.144931055082, 0.25600265256), (-0.24846835011, -0.863593022975, -0.438714679105), (0.157498723291, -0.482910012261, 0.861389616968)167.543084191, 168.932906355, 22.1048211893
4given(-0.955750018673, 0.14492670463, 0.256004203269), (-0.248465620747, -0.863592652243, -0.438716954652), (0.157501546383, -0.48291198088, 0.861387997136)167.543279543, 168.932674124, 22.1046997477

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Components

#1: Protein DH1017.IgM FabC constant domain / Immunoglobulin gamma-1 heavy chain NIE / Immunoglobulin gamma-1 heavy chain


Mass: 10830.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): B-LCL cells / Production host: Homo sapiens (human) / References: UniProt: P0DOX5
#2: Protein DH1017.IgM LambdaC constant domain / G lambda-1 / Germline immunoglobulin lambda 1 / Immunoglobulin lambda-like polypeptide 5


Mass: 11361.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGLL5 / Cell line (production host): B-LCL cells / Production host: Homo sapiens (human) / References: UniProt: B9A064
#3: Antibody DH1017.IgM IgH


Mass: 13325.816 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): B-LCL cells / Production host: Homo sapiens (human)
#4: Antibody DH1017.IgM IgL


Mass: 11482.750 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): B-LCL cells / Production host: Homo sapiens (human)
#5: Protein Core protein / Capsid / Envelope protein E / Flavivirin protease NS2B regulatory subunit / Flavivirin protease NS3 ...Envelope protein E / Flavivirin protease NS2B regulatory subunit / Flavivirin protease NS3 catalytic subunit / Genome polyprotein / Matrix protein / Non-structural protein 1 / Non-structural protein 2A / Non-structural protein 2B / Non-structural protein 3 / Non-structural protein 4A / Non-structural protein 4B / Peptide 2k / Peptide pr / Protein prM / RNA-directed RNA polymerase NS5 / Serine protease NS3 / Serine protease subunit NS2B / Small envelope protein M


Mass: 42623.277 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Zika virus
References: UniProt: A0A2Z2EX91, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase

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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: Zika virus / Type: VIRUS / Entity ID: all / Source: NATURAL
Source (natural)Organism: Zika virus
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 8
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 FIELDBright-field microscopy
Image recordingElectron dose: 35 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 5.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4104 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 363.58 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00157403
ELECTRON MICROSCOPYf_angle_d0.53299238
ELECTRON MICROSCOPYf_chiral_restr00
ELECTRON MICROSCOPYf_plane_restr0.00191844
ELECTRON MICROSCOPYf_dihedral_angle_d4.26781844
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2GELECTRON MICROSCOPYNCS constraints0.000699239283596
ens_1d_3GELECTRON MICROSCOPYNCS constraints0.000703693380913
ens_2d_2CELECTRON MICROSCOPYNCS constraints0.000691649686156
ens_3d_2KELECTRON MICROSCOPYNCS constraints0.000700187189918

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