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- EMDB-23629: Cryo-EM structure of the HCMV pentamer bound by human neuropilin 2 -

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Basic information

Entry
Database: EMDB / ID: EMD-23629
TitleCryo-EM structure of the HCMV pentamer bound by human neuropilin 2
Map dataFocused refinement map, calculated in cryoSPARC and sharpened using DeepEMhancer.
Sample
  • Complex: The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of human neuropilin 2
    • Complex: The ectodomain of the HCMV pentamer
      • Protein or peptide: Envelope protein UL128
      • Protein or peptide: Envelope glycoprotein UL130
      • Protein or peptide: UL131A
    • Complex: Domains a1a2b1b2 of human neuropilin 2
      • Protein or peptide: Neuropilin-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
KeywordsHCMV pentamer / NRP2 / cytomegalovirus / host receptor / VIRAL PROTEIN / VIRAL PROTEIN-HOST RECEPTOR complex
Function / homology
Function and homology information


vestibulocochlear nerve structural organization / dorsal root ganglion morphogenesis / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / trigeminal nerve structural organization / sensory neuron axon guidance / facial nerve structural organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus ...vestibulocochlear nerve structural organization / dorsal root ganglion morphogenesis / ventral trunk neural crest cell migration / sympathetic neuron projection guidance / facioacoustic ganglion development / trigeminal ganglion development / trigeminal nerve structural organization / sensory neuron axon guidance / facial nerve structural organization / gonadotrophin-releasing hormone neuronal migration to the hypothalamus / branchiomotor neuron axon guidance / axon extension involved in axon guidance / sympathetic neuron projection extension / NrCAM interactions / Neurophilin interactions with VEGF and VEGFR / neural crest cell migration involved in autonomic nervous system development / sympathetic ganglion development / vascular endothelial growth factor receptor activity / nerve development / semaphorin receptor complex / semaphorin receptor activity / outflow tract septum morphogenesis / regulation of postsynapse organization / negative chemotaxis / growth factor binding / cytokine binding / semaphorin-plexin signaling pathway / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / axon guidance / cellular response to leukemia inhibitory factor / signaling receptor activity / heparin binding / angiogenesis / postsynaptic membrane / cell adhesion / axon / viral envelope / glutamatergic synapse / extracellular region / metal ion binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Herpesvirus UL130, cytomegalovirus / HCMV glycoprotein pUL130 / Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain, meprin/A5/mu / MAM domain ...Herpesvirus UL130, cytomegalovirus / HCMV glycoprotein pUL130 / Neuropilin / Neuropilin, C-terminal / C-terminal domain of neuropilin glycoprotein / Domain in meprin, A5, receptor protein tyrosine phosphatase mu (and others) / : / Coagulation factors 5/8 type C domain (FA58C) signature 2. / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 1. / CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Coagulation factor 5/8 C-terminal domain, discoidin domain / Coagulation factors 5/8 type C domain (FA58C) profile. / F5/8 type C domain / Coagulation factor 5/8 C-terminal domain / Galactose-binding-like domain superfamily / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Envelope glycoprotein UL130 / UL128 / Neuropilin-2 / UL131A
Similarity search - Component
Biological speciesHuman betaherpesvirus 5 / Homo sapiens (human) / Human cytomegalovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.65 Å
AuthorsWrapp D / McLellan JS
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 15, 2021-
Header (metadata) releaseAug 11, 2021-
Map releaseAug 11, 2021-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with fitted model
  • Atomic models: PDB-7m22
  • Surface level: 0.17
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-7m22
  • Surface level: 0.17
  • Imaged by UCSF Chimera
  • Download
  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7m22
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23629.png

Downloads & links

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Map

FileDownload / File: emd_23629.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused refinement map, calculated in cryoSPARC and sharpened using DeepEMhancer.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 384 pix.
= 412.032 Å		1.07 Å/pix.
x 384 pix.
= 412.032 Å		1.07 Å/pix.
x 384 pix.
= 412.032 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.073 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.17 / Movie #1: 0.17
Minimum - Maximum-0.0433535 - 2.5595467
Average (Standard dev.)0.00009640274 (±0.011446471)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 412.03198 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0731.0731.073
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z412.032412.032412.032
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ400400400
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0432.5600.000

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Supplemental data

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Additional map: Full map that was subsequently subjected to focused...

Fileemd_23629_additional_1.map
AnnotationFull map that was subsequently subjected to focused refinement. Calculated in cryoSPARC and sharpened using DeepEMhancer.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map B for focused refinement.

Fileemd_23629_half_map_1.map
AnnotationHalf-map B for focused refinement.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half-map A for focused refinement.

Fileemd_23629_half_map_2.map
AnnotationHalf-map A for focused refinement.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of ...

EntireName: The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of human neuropilin 2
Components
  • Complex: The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of human neuropilin 2
    • Complex: The ectodomain of the HCMV pentamer
      • Protein or peptide: Envelope protein UL128
      • Protein or peptide: Envelope glycoprotein UL130
      • Protein or peptide: UL131A
    • Complex: Domains a1a2b1b2 of human neuropilin 2
      • Protein or peptide: Neuropilin-2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION

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Supramolecule #1: The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of ...

SupramoleculeName: The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of human neuropilin 2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: The primary map is the result of a focused refinement that encompasses the HCMV UL proteins (UL128, UL130, UL131) and NRP2 domains a2b1b2. The included additional map is the non-focused ...Details: The primary map is the result of a focused refinement that encompasses the HCMV UL proteins (UL128, UL130, UL131) and NRP2 domains a2b1b2. The included additional map is the non-focused refinement in which the entire HCMV pentamer ectodomain and the entirety of NRP2 a1a2b1b2 can be observed.
Molecular weightTheoretical: 230 KDa

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Supramolecule #2: The ectodomain of the HCMV pentamer

SupramoleculeName: The ectodomain of the HCMV pentamer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Human betaherpesvirus 5

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Supramolecule #3: Domains a1a2b1b2 of human neuropilin 2

SupramoleculeName: Domains a1a2b1b2 of human neuropilin 2 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Envelope protein UL128

MacromoleculeName: Envelope protein UL128 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human cytomegalovirus
Molecular weightTheoretical: 16.684299 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EECCEFINVN HPPERCYDFK MCNRFTVALR CPDGEVCYSP EKTAEIRGIV TTMTHSLTRQ VVHNKLTSCN YNPLYLEADG RIRCGKVND KAQYLLGAAG SVPYRWINLE YDKITRIVGL DQYLESVKKH KRLDVCRAKM GYMLQ

UniProtKB: UL128

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Macromolecule #2: Envelope glycoprotein UL130

MacromoleculeName: Envelope glycoprotein UL130 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human cytomegalovirus
Molecular weightTheoretical: 21.761678 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SPWSTLTANQ NPSPPWSKLT YSKPHDAATF YCPFLYPSPP RSPLQFSGFQ QVSTGPECRN ETLYLLYNRE GQTLVERSST WVKKVIWYL SGRNQTILQR MPQTASKPSD GNVQISVEDA KIFGAHMVPK QTKLLRFVVN DGTRYQMCVM KLESWAHVFR D YSVSFQVR LTFTEANNQT YTFCTHPNLI V

UniProtKB: Envelope glycoprotein UL130

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Macromolecule #3: UL131A

MacromoleculeName: UL131A / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human cytomegalovirus
Molecular weightTheoretical: 13.005457 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QCQRETAEKN DYYRVPHYWD ACSRALPDQT RYKYVEQLVD LTLNYHYDAS HGLDNFDVLK RINVTEVSLL ISDFRRQNRR GGTNKRTTF NAAGSLAPHA RSLEFSVRLF AN

UniProtKB: UL131A

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Macromolecule #4: Neuropilin-2

MacromoleculeName: Neuropilin-2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.430434 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QPDPPCGGRL NSKDAGYITS PGYPQDYPSH QNCEWIVYAP EPNQKIVLNF NPHFEIEKHD CKYDFIEIRD GDSESADLLG KHCGNIAPP TIISSGSMLY IKFTSDYARQ GAGFSLRYEI FKTGSEDCSK NFTSPNGTIE SPGFPEKYPH NLDCTFTILA K PKMEIILQ ...String:
QPDPPCGGRL NSKDAGYITS PGYPQDYPSH QNCEWIVYAP EPNQKIVLNF NPHFEIEKHD CKYDFIEIRD GDSESADLLG KHCGNIAPP TIISSGSMLY IKFTSDYARQ GAGFSLRYEI FKTGSEDCSK NFTSPNGTIE SPGFPEKYPH NLDCTFTILA K PKMEIILQ FLIFDLEHDP LQVGEGDCKY DWLDIWDGIP HVGPLIGKYC GTKTPSELRS STGILSLTFH TDMAVAKDGF SA RYYLVHQ EPLENFQCNV PLGMESGRIA NEQISASSTY SDGRWTPQQS RLHGDDNGWT PNLDSNKEYL QVDLRFLTML TAI ATQGAI SRETQNGYYV KSYKLEVSTN GEDWMVYRHG KNHKVFQANN DATEVVLNKL HAPLLTRFVR IRPQTWHSGI ALRL ELFGC RVTDAPCSNM LGMLSGLIAD SQISASSTQE YLWSPSAARL VSSRSGWFPR IPQAQPGEEW LQVDLGTPKT VKGVI IQGA RGGDSITAVE ARAFVRKFKV SYSLNGKDWE YIQDPRTQQP KLFEGNMHYD TPDIRRFDPI PAQYVRVYPE RWSPAG IGM RLEVLGCDWT GSLEVLFQ

UniProtKB: Neuropilin-2

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.4 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
2.0 mMC4H11NO3Tris
200.0 mMNaClsodium chloride
2.0 mMCaCl2calcium chloride
0.02 %NaN3sodium azide
0.1 %(C6.2H10.3O1.35N0.65Na0.35)~72amphipol A8-35
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: Grid was blotted with a force of -6 for 3 seconds.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
DetailsCollected from a single grid at -30 degrees tilt
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 745025
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 203130
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

5vob

source_name: PDB, initial_model_type: experimental model

2qqk

source_name: PDB, initial_model_type: experimental model
Output model

PDB-7m22:
Cryo-EM structure of the HCMV pentamer bound by human neuropilin 2

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