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- EMDB-20735: Cryo-EM structure of CH235UCA bound to Man5-enriched CH505.N279K.... -

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Basic information

Entry
Database: EMDB / ID: EMD-20735
TitleCryo-EM structure of CH235UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664
Map dataRefined and sharpened map from Cryosparc
Sample
  • Complex: Complex of the CH235 unmutated common ancestor (UCA) bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664
    • Protein or peptide: CH235 UCA heavy chain Fab
    • Protein or peptide: CH505.N279K.G458Y.SOSIP.664 gp41
    • Protein or peptide: CH235 UCA light chain Fab
  • Protein or peptide: CH505.N279K.G458Y.SOSIP.664 gp120
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope ...positive regulation of plasma membrane raft polarization / positive regulation of receptor clustering / positive regulation of establishment of T cell polarity / virus-mediated perturbation of host defense response / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / structural molecule activity / virion attachment to host cell / host cell plasma membrane / virion membrane / plasma membrane
Similarity search - Function
Envelope glycoprotein Gp160 / Retroviral envelope protein / Retroviral envelope protein GP41-like / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120
Similarity search - Domain/homology
Envelope glycoprotein gp160 / Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsAcharya P
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 AI145687-01 United States
CitationJournal: PLoS Pathog / Year: 2019
Title: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.
Authors: Celia C LaBranche / Rory Henderson / Allen Hsu / Shay Behrens / Xuejun Chen / Tongqing Zhou / Kevin Wiehe / Kevin O Saunders / S Munir Alam / Mattia Bonsignori / Mario J Borgnia / Quentin J ...Authors: Celia C LaBranche / Rory Henderson / Allen Hsu / Shay Behrens / Xuejun Chen / Tongqing Zhou / Kevin Wiehe / Kevin O Saunders / S Munir Alam / Mattia Bonsignori / Mario J Borgnia / Quentin J Sattentau / Amanda Eaton / Kelli Greene / Hongmei Gao / Hua-Xin Liao / Wilton B Williams / James Peacock / Haili Tang / Lautaro G Perez / Robert J Edwards / Thomas B Kepler / Bette T Korber / Peter D Kwong / John R Mascola / Priyamvada Acharya / Barton F Haynes / David C Montefiori /
Abstract: The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 ...The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.
History
DepositionSep 19, 2019-
Header (metadata) releaseOct 2, 2019-
Map releaseOct 2, 2019-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.364433674
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.364433674
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6uda
  • Surface level: 0.364433674
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20735.png

Downloads & links

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Map

FileDownload / File: emd_20735.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRefined and sharpened map from Cryosparc
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.7 / Movie #1: 0.3644337
Minimum - Maximum-0.69792444 - 2.0413842
Average (Standard dev.)0.0038763084 (±0.074728735)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z345.600345.600345.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.6982.0410.004

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Supplemental data

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Additional map: Refined map from cryosparc sharpened in Phenix

Fileemd_20735_additional.map
AnnotationRefined map from cryosparc sharpened in Phenix
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of the CH235 unmutated common ancestor (UCA) bound to Man...

EntireName: Complex of the CH235 unmutated common ancestor (UCA) bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664
Components
  • Complex: Complex of the CH235 unmutated common ancestor (UCA) bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664
    • Protein or peptide: CH235 UCA heavy chain Fab
    • Protein or peptide: CH505.N279K.G458Y.SOSIP.664 gp41
    • Protein or peptide: CH235 UCA light chain Fab
  • Protein or peptide: CH505.N279K.G458Y.SOSIP.664 gp120
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of the CH235 unmutated common ancestor (UCA) bound to Man...

SupramoleculeName: Complex of the CH235 unmutated common ancestor (UCA) bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#4
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 360 KDa

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Macromolecule #1: CH505.N279K.G458Y.SOSIP.664 gp120

MacromoleculeName: CH505.N279K.G458Y.SOSIP.664 gp120 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 54.546402 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPMGSLQPLA TLYLLGMLVA SVLAAENLWV TVYYGVPVWK EAKTTLFCAS DAKAYEKEVH NVWATHACVP TDPNPQEMVL KNVTENFNM WKNDMVDQMH EDVISLWDQS LKPCVKLTPL CVTLNCTNAT ASNSSIIEGM KNCSFNITTE LRDKREKKNA L FYKLDIVQ ...String:
MPMGSLQPLA TLYLLGMLVA SVLAAENLWV TVYYGVPVWK EAKTTLFCAS DAKAYEKEVH NVWATHACVP TDPNPQEMVL KNVTENFNM WKNDMVDQMH EDVISLWDQS LKPCVKLTPL CVTLNCTNAT ASNSSIIEGM KNCSFNITTE LRDKREKKNA L FYKLDIVQ LDGNSSQYRL INCNTSVITQ ACPKVSFDPI PIHYCAPAGY AILKCNNKTF TGTGPCNNVS TVQCTHGIKP VV STQLLLN GSLAEGEIII RSENITKNVK TIIVHLNESV KIECTRPNNK TRTSIRIGPG QAFYATGQVI GDIREAYCNI NES KWNETL QRVSKKLKEY FPHKNITFQP SSGGDLEITT HSFNCGGEFF YCNTSSLFNR TYMANSTDMA NSTETNSTRT ITIH CRIKQ IINMWQEVGR AMYAPPIAGN ITCISNITGL LLTRDYGKNN TETFRPGGGN MKDNWRSELY KYKVVKIEPL GVAPT RCKR RVV

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Macromolecule #2: CH235 UCA heavy chain Fab

MacromoleculeName: CH235 UCA heavy chain Fab / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.635938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DQVQLVQSGA EVKKPGASVK VSCKASGYTF TSYYMHWVRQ APGQGLEWMG IINPSGGSTS YAQKFQGRV TMTRDTSTST VYMELSSLRS EDTAVYYCAR DVGTEGSLLH FDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL ...String:
METDTLLLWV LLLWVPGSTG DQVQLVQSGA EVKKPGASVK VSCKASGYTF TSYYMHWVRQ APGQGLEWMG IINPSGGSTS YAQKFQGRV TMTRDTSTST VYMELSSLRS EDTAVYYCAR DVGTEGSLLH FDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KR VEPKSCD KT

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Macromolecule #3: CH505.N279K.G458Y.SOSIP.664 gp41

MacromoleculeName: CH505.N279K.G458Y.SOSIP.664 gp41 / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 18.146699 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GRRRRRRAVG IGAVFLGFLG AAGSTMGAAS MTLTVQARNL LSGIVQQQSN LLRAPEAQQH LLKLTVWGIK QLQARVLAVE RYLRDQQLL GIWGCSGKLI CCTNVPWNSS WSNRNLSEIW DNMTWLQWDK EISNYTQIIY GLLEESQNQQ EKNEQDLLAL D

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Macromolecule #4: CH235 UCA light chain Fab

MacromoleculeName: CH235 UCA light chain Fab / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.65957 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSG TEFTLTISSL QSEDFAVYYC QQYNNWWTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW ...String:
METDTLLLWV LLLWVPGSTG DEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSG TEFTLTISSL QSEDFAVYYC QQYNNWWTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration1.5 mg/mL
BufferpH: 7.2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 42.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: Gctf
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 22093

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