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

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Basic information

Entry
Database: PDB / ID: 7m22
TitleCryo-EM structure of the HCMV pentamer bound by human neuropilin 2
Components
  • Envelope glycoprotein UL130
  • Envelope protein UL128
  • Neuropilin-2
  • UL131A
KeywordsVIRAL PROTEIN/HOST RECEPTOR / HCMV 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 / sympathetic ganglion development / neural crest cell migration involved in autonomic nervous system development / vascular endothelial growth factor receptor activity / nerve development / outflow tract septum morphogenesis / semaphorin receptor activity / semaphorin receptor complex / regulation of postsynapse organization / negative chemotaxis / cytokine binding / growth factor binding / semaphorin-plexin signaling pathway / positive regulation of endothelial cell proliferation / positive regulation of endothelial cell migration / cellular response to leukemia inhibitory factor / axon guidance / signaling receptor activity / heparin binding / postsynaptic membrane / angiogenesis / cell adhesion / axon / glutamatergic synapse / viral envelope / extracellular region / identical protein binding / membrane / metal ion binding / 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) / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 2. ...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) / MAM domain, meprin/A5/mu / MAM domain / MAM domain profile. / Coagulation factors 5/8 type C domain (FA58C) signature 2. / 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 cytomegalovirus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 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
DepositionMar 15, 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 / _citation_author.identifier_ORCID / _citation_author.name

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Assembly

Deposited unit
C: Envelope protein UL128
D: Envelope glycoprotein UL130
E: UL131A
N: Neuropilin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,3647
Polymers116,8824
Non-polymers4823
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 4 molecules CDEN

#1: Protein Envelope protein UL128 / UL128


Mass: 16684.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Gene: UL128 / Production host: Homo sapiens (human) / References: UniProt: C8BLJ3
#2: Protein Envelope glycoprotein UL130 / ORFL272C_UL130 / UL130 protein


Mass: 21761.678 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Gene: UL130 / Production host: Homo sapiens (human) / References: UniProt: A0A0G2TB82
#3: Protein UL131A


Mass: 13005.457 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human cytomegalovirus / Production host: Homo sapiens (human) / References: UniProt: Q38M21
#4: Protein Neuropilin-2 / Vascular endothelial cell growth factor 165 receptor 2


Mass: 65430.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRP2, VEGF165R2 / Production host: Homo sapiens (human) / References: UniProt: O60462

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Sugars / Non-polymers , 2 types, 3 molecules

#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestN

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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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1The ectodomain of the HCMV pentamer bound by domains a1a2b1b2 of human neuropilin 2COMPLEXThe 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.#1-#40MULTIPLE SOURCES
2The ectodomain of the HCMV pentamerCOMPLEX#1-#31RECOMBINANT
3Domains a1a2b1b2 of human neuropilin 2COMPLEX#41RECOMBINANT
Molecular weightValue: 0.23 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Human betaherpesvirus 510359
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
12 mMTrisC4H11NO31
2200 mMsodium chlorideNaCl1
32 mMcalcium chlorideCaCl21
40.02 %sodium azideNaN31
50.1 %amphipol A8-35(C6.2H10.3O1.35N0.65Na0.35)~721
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K / Details: Grid was blotted with a force of -6 for 3 seconds

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Details: Collected from a single grid at -30 degrees tilt
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
4WarpCTF correction
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 745025
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203130 / Symmetry type: POINT
Atomic model building
IDPDB-ID 3D fitting-ID
15VOB

5vob

1
22QQK

2qqk

1

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