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- PDB-7kba: Crystal structure of the HCMV pentamer-specific Fab 2-18 -

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Basic information

Entry
Database: PDB / ID: 7kba
TitleCrystal structure of the HCMV pentamer-specific Fab 2-18
Components
  • 2-18 Fab Heavy Chain
  • 2-18 Fab Light Chain
KeywordsANTIVIRAL PROTEIN / IMMUNE SYSTEM / Antibody / HCMV / Fab
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsWrapp, D. / 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
DepositionOct 1, 2020Deposition 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 2-18 Fab Heavy Chain
B: 2-18 Fab Light Chain
H: 2-18 Fab Heavy Chain
L: 2-18 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)98,0734
Polymers98,0734
Non-polymers00
Water1,26170
1
A: 2-18 Fab Heavy Chain
B: 2-18 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)49,0372
Polymers49,0372
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3560 Å2
ΔGint-25 kcal/mol
Surface area19550 Å2
MethodPISA
2
H: 2-18 Fab Heavy Chain
L: 2-18 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)49,0372
Polymers49,0372
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3640 Å2
ΔGint-26 kcal/mol
Surface area19550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)130.080, 59.103, 141.927
Angle α, β, γ (deg.)90.000, 91.450, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Antibody 2-18 Fab Heavy Chain


Mass: 25622.490 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody 2-18 Fab Light Chain


Mass: 23414.055 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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.78 Å3/Da / Density % sol: 55.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: Seed crystals were grown in 0.1M HEPES pH 7.5, 45% PEG 400. Crystals were then seeded into 0.2M ammonium acetate, 0.1M sodium citrate tribasic dihydrate pH 5.6, 30% PEG 4000

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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 315 / Detector: CCD / Date: Oct 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.8→65.02 Å / Num. obs: 26602 / % possible obs: 98.8 % / Redundancy: 4.1 % / CC1/2: 0.851 / Net I/σ(I): 4
Reflection shellResolution: 2.8→2.95 Å / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3773 / CC1/2: 0.291 / % possible all: 96.7

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIXdev_3758refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5IHZ, 6MEE

5ihz

6mee


Resolution: 2.8→65.02 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 24.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2566 1262 4.77 %
Rwork0.222 25205 -
obs0.2236 26467 98.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 120.86 Å2 / Biso mean: 27.0221 Å2 / Biso min: 3.99 Å2
Refinement stepCycle: final / Resolution: 2.8→65.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6726 0 0 70 6796
Biso mean---27.11 -
Num. residues----887
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086892
X-RAY DIFFRACTIONf_angle_d1.4279364
X-RAY DIFFRACTIONf_dihedral_angle_d10.909962
X-RAY DIFFRACTIONf_chiral_restr0.0741042
X-RAY DIFFRACTIONf_plane_restr0.0111210
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-2.910.35851250.31892608273392
2.91-3.040.31031620.29482766292899
3.04-3.210.3071660.260127972963100
3.21-3.410.30781110.25272853296499
3.41-3.670.26461490.23232762291198
3.67-4.040.26571360.210628212957100
4.04-4.620.18831370.18142836297399
4.62-5.820.2111300.17222858298899
5.82-65.020.22761460.19522904305098

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