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- PDB-8tzn: Crystal structure of 10E8-GT10.2 HIV-1 MPER scaffold in complex w... -

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Basic information

Entry
Database: PDB / ID: 8tzn
TitleCrystal structure of 10E8-GT10.2 HIV-1 MPER scaffold in complex with a non-human primate W3-01 Fab
Components
  • 10E8-GT10.2 MPER scaffold
  • W3-01 Fab Heavy Chain
  • W3-01 Fab Light Chain
KeywordsIMMUNE SYSTEM / HIV-1 / MPER / NHP / 10E8 / scaffold / GP41
Biological speciesunidentified monkey (mammal)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.11 Å
AuthorsLee, C.C.D. / Wilson, I.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)UM1 AI144462 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI147826 United States
Bill & Melinda Gates FoundationNAC CAVD United States
CitationJournal: Nat Immunol / Year: 2024
Title: Vaccination induces broadly neutralizing antibody precursors to HIV gp41.
Authors: Torben Schiffner / Ivy Phung / Rashmi Ray / Adriana Irimia / Ming Tian / Olivia Swanson / Jeong Hyun Lee / Chang-Chun D Lee / Ester Marina-Zárate / So Yeon Cho / Jiachen Huang / Gabriel ...Authors: Torben Schiffner / Ivy Phung / Rashmi Ray / Adriana Irimia / Ming Tian / Olivia Swanson / Jeong Hyun Lee / Chang-Chun D Lee / Ester Marina-Zárate / So Yeon Cho / Jiachen Huang / Gabriel Ozorowski / Patrick D Skog / Andreia M Serra / Kimmo Rantalainen / Joel D Allen / Sabyasachi Baboo / Oscar L Rodriguez / Sunny Himansu / Jianfu Zhou / Jonathan Hurtado / Claudia T Flynn / Katherine McKenney / Colin Havenar-Daughton / Swati Saha / Kaitlyn Shields / Steven Schultze / Melissa L Smith / Chi-Hui Liang / Laura Toy / Simone Pecetta / Ying-Cing Lin / Jordan R Willis / Fabian Sesterhenn / Daniel W Kulp / Xiaozhen Hu / Christopher A Cottrell / Xiaoya Zhou / Jennifer Ruiz / Xuesong Wang / Usha Nair / Kathrin H Kirsch / Hwei-Ling Cheng / Jillian Davis / Oleksandr Kalyuzhniy / Alessia Liguori / Jolene K Diedrich / Julia T Ngo / Vanessa Lewis / Nicole Phelps / Ryan D Tingle / Skye Spencer / Erik Georgeson / Yumiko Adachi / Michael Kubitz / Saman Eskandarzadeh / Marc A Elsliger / Rama R Amara / Elise Landais / Bryan Briney / Dennis R Burton / Diane G Carnathan / Guido Silvestri / Corey T Watson / John R Yates / James C Paulson / Max Crispin / Gevorg Grigoryan / Andrew B Ward / Devin Sok / Frederick W Alt / Ian A Wilson / Facundo D Batista / Shane Crotty / William R Schief /
Abstract: A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design ...A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
History
DepositionAug 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: 10E8-GT10.2 MPER scaffold
G: W3-01 Fab Heavy Chain
H: W3-01 Fab Light Chain
A: 10E8-GT10.2 MPER scaffold
B: W3-01 Fab Heavy Chain
D: W3-01 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)139,0086
Polymers139,0086
Non-polymers00
Water00
1
C: 10E8-GT10.2 MPER scaffold
G: W3-01 Fab Heavy Chain
H: W3-01 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)69,5043
Polymers69,5043
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: 10E8-GT10.2 MPER scaffold
B: W3-01 Fab Heavy Chain
D: W3-01 Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)69,5043
Polymers69,5043
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.825, 111.825, 199.609
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3
#4: x-y,-y,-z+1/3
#5: -x,-x+y,-z+2/3
#6: y,x,-z

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Components

#1: Protein 10E8-GT10.2 MPER scaffold


Mass: 21826.258 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified monkey (mammal) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#2: Antibody W3-01 Fab Heavy Chain


Mass: 24680.521 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified monkey (mammal) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
#3: Antibody W3-01 Fab Light Chain


Mass: 22997.334 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified monkey (mammal) / Cell line (production host): HEK293 / Production host: Homo sapiens (human)
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: 2.59 Å3/Da / Density % sol: 52.54 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 0.2M ammonium dihydrogen phosphate, 20% PEG3350, and 10% (v/v) ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 3.11→50 Å / Num. obs: 26452 / % possible obs: 100 % / Redundancy: 17.7 % / Biso Wilson estimate: 101.75 Å2 / CC1/2: 1 / Net I/σ(I): 16.7
Reflection shellResolution: 3.11→3.17 Å / Num. unique obs: 2590 / CC1/2: 0.492

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Processing

Software
NameVersionClassification
PHENIX1.21rc1_5058refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.11→39.15 Å / SU ML: 0.4674 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.6121
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2836 1327 5.22 %
Rwork0.2462 24105 -
obs0.2482 25432 95.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 117.07 Å2
Refinement stepCycle: LAST / Resolution: 3.11→39.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7279 0 0 0 7279
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01087458
X-RAY DIFFRACTIONf_angle_d1.218210147
X-RAY DIFFRACTIONf_chiral_restr0.05721124
X-RAY DIFFRACTIONf_plane_restr0.00981293
X-RAY DIFFRACTIONf_dihedral_angle_d12.00122677
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.11-3.240.35791310.32272459X-RAY DIFFRACTION89.84
3.24-3.390.36871430.29932508X-RAY DIFFRACTION91.19
3.39-3.560.3031590.28282578X-RAY DIFFRACTION94.25
3.56-3.790.31131550.25242630X-RAY DIFFRACTION96.23
3.79-4.080.27891390.23532688X-RAY DIFFRACTION96.55
4.08-4.490.28241720.22552726X-RAY DIFFRACTION98.3
4.49-5.140.23481410.2182766X-RAY DIFFRACTION99.01
5.14-6.470.28781460.24792812X-RAY DIFFRACTION98.76
6.47-39.150.27421410.24752938X-RAY DIFFRACTION98.53
Refinement TLS params.Method: refined / Origin x: -36.028005886 Å / Origin y: -0.0207168551643 Å / Origin z: 8.1983845601 Å
111213212223313233
T1.11776477765 Å2-0.166608798474 Å20.0545048579307 Å2-0.568336132625 Å20.00320831979287 Å2--0.748333424771 Å2
L0.608589761925 °2-0.0229050303484 °20.00165540884067 °2-0.784744752829 °2-0.390712573267 °2--1.33266945501 °2
S-0.261375143293 Å °0.226266814902 Å °-0.0851065966642 Å °-0.338451297007 Å °0.107902312397 Å °-0.0854470419364 Å °0.406892340139 Å °0.198066861079 Å °0.13780794104 Å °
Refinement TLS groupSelection details: all

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