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- PDB-5f96: Crystal structure of broadly neutralizing VH1-46 germline-derived... -

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Entry
Database: PDB / ID: 5f96
TitleCrystal structure of broadly neutralizing VH1-46 germline-derived CD4-binding site-directed antibody CH235.12 in complex with HIV-1 clade A/E 93TH057 gp120
Components
  • HEAVY CHAIN OF ANTIBODY CH235.12
  • LIGHT CHAIN OF ANTIBODY CH235.12
  • clade A/E 93TH057 HIV-1 gp120 core
KeywordsIMMUNE SYSTEM / HIV-1 / Antibody / CH235 lineage / VH1-46 germline
Function / homology
Function and homology information


HIV Envelope Protein Gp120; Chain G / Human immunodeficiency virus 1, Gp160, envelope glycoprotein / Gp120 core superfamily / Envelope glycoprotein GP120 / Human immunodeficiency virus 1, envelope glycoprotein Gp120 / Beta Complex / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
clade A/E 93TH057 HIV-1 gp120 core
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2407 Å
AuthorsZhou, T. / Kwong, P.D.
CitationJournal: Cell / Year: 2016
Title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody.
Authors: Mattia Bonsignori / Tongqing Zhou / Zizhang Sheng / Lei Chen / Feng Gao / M Gordon Joyce / Gabriel Ozorowski / Gwo-Yu Chuang / Chaim A Schramm / Kevin Wiehe / S Munir Alam / Todd Bradley / ...Authors: Mattia Bonsignori / Tongqing Zhou / Zizhang Sheng / Lei Chen / Feng Gao / M Gordon Joyce / Gabriel Ozorowski / Gwo-Yu Chuang / Chaim A Schramm / Kevin Wiehe / S Munir Alam / Todd Bradley / Morgan A Gladden / Kwan-Ki Hwang / Sheelah Iyengar / Amit Kumar / Xiaozhi Lu / Kan Luo / Michael C Mangiapani / Robert J Parks / Hongshuo Song / Priyamvada Acharya / Robert T Bailer / Allen Cao / Aliaksandr Druz / Ivelin S Georgiev / Young D Kwon / Mark K Louder / Baoshan Zhang / Anqi Zheng / Brenna J Hill / Rui Kong / Cinque Soto / / James C Mullikin / Daniel C Douek / David C Montefiori / Michael A Moody / George M Shaw / Beatrice H Hahn / Garnett Kelsoe / Peter T Hraber / Bette T Korber / Scott D Boyd / Andrew Z Fire / Thomas B Kepler / Lawrence Shapiro / Andrew B Ward / John R Mascola / Hua-Xin Liao / Peter D Kwong / Barton F Haynes /
Abstract: Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling ...Antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. Here, we define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. We integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.
History
DepositionDec 9, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references
Revision 1.2Apr 20, 2016Group: Database references
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations / Category: pdbx_database_related / pdbx_struct_oper_list / Item: _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_role
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
G: clade A/E 93TH057 HIV-1 gp120 core
H: HEAVY CHAIN OF ANTIBODY CH235.12
L: LIGHT CHAIN OF ANTIBODY CH235.12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,35118
Polymers86,9823
Non-polymers3,36915
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5490 Å2
ΔGint-23 kcal/mol
Surface area34320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.659, 69.869, 127.272
Angle α, β, γ (deg.)90.000, 94.610, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Antibody , 2 types, 2 molecules HL

#2: Antibody HEAVY CHAIN OF ANTIBODY CH235.12


Mass: 24319.373 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pVRC8400 / Details (production host): CMVR-based / Cell line (production host): 293F / Production host: Homo sapiens (human)
#3: Antibody LIGHT CHAIN OF ANTIBODY CH235.12


Mass: 23450.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pVRC8400 / Details (production host): CMVR-based / Cell line (production host): 293F / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 13 molecules G

#1: Protein clade A/E 93TH057 HIV-1 gp120 core


Mass: 39211.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: HIV-1 Env / Plasmid: pVRC8400 / Details (production host): CMVR-based / Cell line (production host): HEK293F GNTI-/- / Production host: Homo sapiens (human) / References: UniProt: A0A0M3KKW9
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 12
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

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Non-polymers , 2 types, 199 molecules

#5: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 196 / Source method: isolated from a natural source / Formula: H2O

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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: 2.73 Å3/Da / Density % sol: 55.01 % / Description: Rods
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 5.5 % PEG 8000, 27% PEG 400, 0.1M HEPES, pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Cryoprotected
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 23, 2015 / Details: Mar300HS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.24→50 Å / Num. obs: 43941 / % possible obs: 97.6 % / Observed criterion σ(I): 2 / Redundancy: 3 % / Rmerge(I) obs: 0.123 / Rsym value: 0.125 / Net I/av σ(I): 15.5 / Net I/σ(I): 15.5
Reflection shellResolution: 2.24→2.29 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.416 / Mean I/σ(I) obs: 2.11 / % possible all: 86.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: CH235-gp120 complex

Resolution: 2.2407→34.549 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2328 1986 4.52 %Random selection
Rwork0.1903 41936 --
obs0.1922 43922 96.95 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 161.25 Å2 / Biso mean: 64.3414 Å2 / Biso min: 31 Å2
Refinement stepCycle: final / Resolution: 2.2407→34.549 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5968 0 213 196 6377
Biso mean--96.48 59.08 -
Num. residues----770
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086354
X-RAY DIFFRACTIONf_angle_d0.9098663
X-RAY DIFFRACTIONf_chiral_restr0.058991
X-RAY DIFFRACTIONf_plane_restr0.0061097
X-RAY DIFFRACTIONf_dihedral_angle_d14.2073790
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2407-2.29680.30831130.2642401251479
2.2968-2.35880.28591400.26232873301393
2.3588-2.42820.35181270.25762987311497
2.4282-2.50660.32311640.25573026319099
2.5066-2.59620.291380.25283070320899
2.5962-2.70010.32461420.24693050319299
2.7001-2.82290.2891480.243630793227100
2.8229-2.97160.27761390.234930573196100
2.9716-3.15770.29961530.23530843237100
3.1577-3.40130.25731380.21343039317799
3.4013-3.74320.22491460.1843059320599
3.7432-4.2840.20661510.16913045319699
4.284-5.39410.16981440.14083079322398
5.3941-34.55310.20691430.1653087323097
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.550.18321.74734.03150.82418.2784-0.00640.12530.3166-0.24270.0532-0.1322-0.53170.3369-0.03970.4183-0.0281-0.02970.34830.0390.491864.26973.498710.2713
27.35985.39930.99345.8765-0.68957.1067-0.99380.95190.6726-1.13370.56021.18010.2353-0.27770.41960.69650.0559-0.15240.3777-0.00540.791151.6162-11.0108-3.5799
30.28870.84740.47638.37072.2063.2217-0.0321-0.17730.20870.0659-0.0684-0.4432-0.41370.52830.11510.2974-0.0944-0.02790.47150.02450.575370.5121.404716.9938
42.69390.3841-0.26492.07331.05719.2357-0.19170.0385-0.3117-0.00220.0032-0.23430.36220.64370.13790.32490.0221-0.02640.34090.05570.457770.9197-17.394810.8932
53.89521.77490.53571.1592-1.4057.1336-0.1887-0.1647-0.33520.0378-0.1978-0.42340.13990.48530.4060.40750.16570.02020.30440.04260.541671.3951-23.490316.9041
67.7517-2.83940.59434.5506-0.00547.4671-0.16750.3405-0.3653-0.333-0.1197-0.04150.52410.48940.25790.4875-0.10770.11150.3192-0.00910.410863.1019-23.38512.3876
75.80841.8532-2.50853.74670.97632.09480.0658-0.3187-0.43610.4368-0.10190.05420.12280.33810.1160.28610.0911-0.06510.3782-0.01010.456768.4741-23.196518.2751
86.79965.16553.38329.25927.70368.53950.6177-0.258-0.38890.324-0.4741-0.31090.3959-0.3826-0.17660.3726-0.0313-0.07850.39390.14350.339964.7393-3.165617.1351
95.3979-2.07830.63715.9783-0.3086.2194-0.24020.6387-0.128-0.30140.00840.49410.3247-0.38590.22010.3948-0.093-0.06210.3888-0.03620.3838.2504-31.583525.3941
106.8215-0.1908-0.29293.3566-4.68476.6964-0.05360.61060.6854-0.41620.22920.97680.1277-0.2114-0.23630.43780.0081-0.06270.31960.01010.338745.5853-20.520425.6618
117.31162.8618-5.97042.1793-0.80137.1119-0.3926-0.3744-0.5042-0.087-0.0333-0.51510.58790.17130.33940.37260.0854-0.09370.2940.01760.356952.6264-28.03327.429
124.50362.4778-1.01645.221.1583.9126-0.26050.4942-0.0259-0.20890.04390.09140.327-0.13810.2470.29010.0255-0.05590.35490.03070.27145.9173-27.519726.7466
134.35393.1073-3.28997.791-1.85872.5015-0.4851-0.028-0.2219-0.273-0.00190.21771.3328-0.47940.44140.36930.0167-0.00640.4070.07940.492229.7664-50.14250.335
142.1940.7107-2.35224.0887-1.86738.0364-0.18660.11430.2689-0.09040.28350.24730.193-0.8146-0.04920.4097-0.0395-0.08310.44490.08580.655423.7446-42.970549.9281
154.45730.6869-3.10415.5602-0.4435.8188-0.1415-0.1464-0.02810.10130.31070.4920.3579-0.3519-0.10180.4584-0.0265-0.02770.46480.03750.636524.3705-49.272552.7085
162.1033-0.1967-0.66685.1501-3.43442.5677-0.3567-1.0152-0.06810.9080.23-0.09610.22440.6850.12310.5174-0.092-0.05770.5818-0.13930.410246.9996-20.81753.1214
173.34651.2878-4.0781.3386-1.61187.76810.1896-0.29520.39220.2915-0.03710.1989-0.41280.1554-0.1620.37410.0331-0.04090.3692-0.07940.429146.5769-17.143846.4807
183.647-0.2769-0.41158.91381.02513.6706-0.0074-0.5642-0.41530.0595-0.1909-0.00140.37990.13610.16650.42730.06790.01430.49850.10330.360537.5272-46.674758.598
194.8675-2.2942-1.31387.97062.76274.479-0.1778-0.3046-0.08420.50110.2252-0.18190.52960.5345-0.0610.40370.05170.0370.47710.05340.321841.4633-45.76459.396
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'G' and (resid 45 through 115 )G0
2X-RAY DIFFRACTION2chain 'G' and (resid 116 through 215 )G0
3X-RAY DIFFRACTION3chain 'G' and (resid 216 through 258 )G0
4X-RAY DIFFRACTION4chain 'G' and (resid 259 through 334 )G0
5X-RAY DIFFRACTION5chain 'G' and (resid 335 through 378 )G0
6X-RAY DIFFRACTION6chain 'G' and (resid 379 through 442 )G0
7X-RAY DIFFRACTION7chain 'G' and (resid 443 through 470 )G0
8X-RAY DIFFRACTION8chain 'G' and (resid 471 through 491 )G0
9X-RAY DIFFRACTION9chain 'H' and (resid 1 through 23 )H0
10X-RAY DIFFRACTION10chain 'H' and (resid 24 through 40 )H0
11X-RAY DIFFRACTION11chain 'H' and (resid 41 through 64 )H0
12X-RAY DIFFRACTION12chain 'H' and (resid 65 through 109 )H0
13X-RAY DIFFRACTION13chain 'H' and (resid 110 through 143 )H0
14X-RAY DIFFRACTION14chain 'H' and (resid 144 through 166 )H0
15X-RAY DIFFRACTION15chain 'H' and (resid 167 through 224 )H0
16X-RAY DIFFRACTION16chain 'L' and (resid 1 through 18 )L0
17X-RAY DIFFRACTION17chain 'L' and (resid 19 through 112 )L0
18X-RAY DIFFRACTION18chain 'L' and (resid 113 through 149 )L0
19X-RAY DIFFRACTION19chain 'L' and (resid 150 through 210 )L0

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