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- PDB-7lyw: Crystal structure of the HCMV pentamer-specific antibody 2-25 -

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Basic information

Entry
Database: PDB / ID: 7lyw
TitleCrystal structure of the HCMV pentamer-specific antibody 2-25
Components
  • 2-25 Fab Heavy Chain
  • 2-25 Fab Light Chain
KeywordsIMMUNE SYSTEM / antibody / Fab / HCMV pentamer / cytomegalovirus
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsWrapp, D. / Mishra, A.K. / McLellan, J.S.
CitationJournal: Sci Adv / Year: 2022
Title: Structural basis for HCMV Pentamer recognition by neuropilin 2 and neutralizing antibodies.
Authors: Daniel Wrapp / Xiaohua Ye / Zhiqiang Ku / Hang Su / Harrison G Jones / Nianshuang Wang / Akaash K Mishra / Daniel C Freed / Fengsheng Li / Aimin Tang / Leike Li / Dabbu Kumar Jaijyan / Hua ...Authors: Daniel Wrapp / Xiaohua Ye / Zhiqiang Ku / Hang Su / Harrison G Jones / Nianshuang Wang / Akaash K Mishra / Daniel C Freed / Fengsheng Li / Aimin Tang / Leike Li / Dabbu Kumar Jaijyan / Hua Zhu / Dai Wang / Tong-Ming Fu / Ningyan Zhang / Zhiqiang An / Jason S McLellan /
Abstract: Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into ...Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into epithelial, endothelial, and myeloid cells by interacting with the cell surface receptor neuropilin 2 (NRP2). Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here, we describe the cryo-EM structure of NRP2 bound to Pentamer. The high-affinity interaction between these proteins is calcium dependent and differs from the canonical carboxyl-terminal arginine (CendR) binding that NRP2 typically uses. We also determine the structures of four neutralizing human antibodies bound to the HCMV Pentamer to define susceptible epitopes. Two of these antibodies compete with NRP2 binding, but the two most potent antibodies recognize a previously unidentified epitope that does not overlap the NRP2-binding site. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization.
History
DepositionMar 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
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
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 2-25 Fab Heavy Chain
B: 2-25 Fab Light Chain
C: 2-25 Fab Heavy Chain
D: 2-25 Fab Light Chain
H: 2-25 Fab Heavy Chain
L: 2-25 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)143,7406
Polymers143,7406
Non-polymers00
Water9,134507
1
A: 2-25 Fab Heavy Chain
B: 2-25 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,9132
Polymers47,9132
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3000 Å2
ΔGint-20 kcal/mol
Surface area19380 Å2
MethodPISA
2
C: 2-25 Fab Heavy Chain
D: 2-25 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,9132
Polymers47,9132
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3030 Å2
ΔGint-19 kcal/mol
Surface area19490 Å2
MethodPISA
3
H: 2-25 Fab Heavy Chain
L: 2-25 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)47,9132
Polymers47,9132
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3060 Å2
ΔGint-21 kcal/mol
Surface area19310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)180.870, 180.870, 138.850
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11B-364-

HOH

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Components

#1: Antibody 2-25 Fab Heavy Chain


Mass: 25189.230 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 2-25 Fab Light Chain


Mass: 22723.951 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 507 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 3.95 Å3/Da / Density % sol: 68.86 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 30% PEG 4000, 0.1M BIS-TRIS pH 6.5, 0.1 M calcium chloride, 0.1 M magnesium chloride

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.51→69.89 Å / Num. obs: 77232 / % possible obs: 98.38 % / Redundancy: 6.8 % / CC1/2: 0.991 / Net I/σ(I): 9.3
Reflection shellResolution: 2.51→2.57 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 7688 / CC1/2: 0.522

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIXdev_3758refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5N4J

5n4j


Resolution: 2.51→58.08 Å / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2189 --
Rwork0.1872 73397 -
obs-77206 98.39 %
Solvent computationSolvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 115.79 Å2 / Biso min: 15.08 Å2
Refinement stepCycle: final / Resolution: 2.51→58.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9633 0 0 507 10140
Biso mean---42.96 -
Num. residues----1272
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0119873
X-RAY DIFFRACTIONf_angle_d1.22613473
X-RAY DIFFRACTIONf_dihedral_angle_d20.5063507
X-RAY DIFFRACTIONf_chiral_restr0.0731518
X-RAY DIFFRACTIONf_plane_restr0.0091719
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.51-2.550.33031150.270727192834100
2.55-2.580.27511350.275727202855100
2.58-2.610.35611540.267727212875100
2.61-2.650.33641440.255227292873100
2.65-2.690.24081330.236227132846100
2.69-2.730.25351450.221826942839100
2.73-2.780.24561080.22652779288799
2.78-2.830.26141470.21622672281999
2.83-2.880.2651330.21692613274696
2.88-2.930.23951190.21192620273995
2.93-2.990.28651360.222927222858100
2.99-3.060.25291600.219427222882100
3.06-3.130.26141450.215527322877100
3.13-3.210.23161740.209626932867100
3.21-3.290.23411230.19772763288699
3.29-3.390.23321470.19442711285899
3.39-3.50.2331510.182699285098
3.5-3.630.20871270.16152566269393
3.63-3.770.19281310.166427632894100
3.77-3.940.21051430.174127572900100
3.94-4.150.17971580.157827622920100
4.15-4.410.18121450.14192765291099
4.41-4.750.16431430.14092573271693
4.75-5.230.17411610.14852751291299
5.23-5.980.18061350.17392814294999
5.98-7.540.20821450.18992708285395
7.54-58.080.22461530.22916306997

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