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- PDB-7r74: Crystal structure of llama VHH antibody in complex with HIV-1 HXB... -

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Basic information

Entry
Database: PDB / ID: 7r74
TitleCrystal structure of llama VHH antibody in complex with HIV-1 HXBC2 gp120 core
Components
  • Antibody C8 VHH domain
  • Glycoprotein 120
KeywordsIMMUNE SYSTEM / Llama / antibody / VHH / HIV-1 / gp120
Biological speciesHuman immunodeficiency virus 1
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.76 Å
AuthorsZhou, T. / Kwong, P.D.
CitationJournal: Structure / Year: 2022
Title: Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site.
Authors: Tongqing Zhou / Lei Chen / Jason Gorman / Shuishu Wang / Young D Kwon / Bob C Lin / Mark K Louder / Reda Rawi / Erik-Stephane D Stancofski / Yongping Yang / Baoshan Zhang / Anna Forsman ...Authors: Tongqing Zhou / Lei Chen / Jason Gorman / Shuishu Wang / Young D Kwon / Bob C Lin / Mark K Louder / Reda Rawi / Erik-Stephane D Stancofski / Yongping Yang / Baoshan Zhang / Anna Forsman Quigley / Laura E McCoy / Lucy Rutten / Theo Verrips / Robin A Weiss / / Nicole A Doria-Rose / Lawrence Shapiro / Peter D Kwong /
Abstract: Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies ...Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies (J3, A12, C8, and D7), all of which targeted the CD4-binding site, in complex with the HIV-1 envelope (Env) gp120 core, and determined a cryoelectron microscopy (cryo-EM) structure of J3 with the Env trimer. Crystal and cryo-EM structures of J3 complexes revealed this nanobody to mimic binding to the prefusion-closed trimer for the primary site of CD4 recognition as well as a secondary quaternary site. In contrast, crystal structures of A12, C8, and D7 with gp120 revealed epitopes that included portions of the gp120 inner domain, inaccessible on the prefusion-closed trimer. Overall, these structures explain the broad and potent neutralization of J3 and limited neutralization of A12, C8, and D7, which utilized binding modes incompatible with the neutralization-targeted prefusion-closed conformation of Env.
History
DepositionJun 24, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycoprotein 120
B: Antibody C8 VHH domain
C: Glycoprotein 120
D: Antibody C8 VHH domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,02222
Polymers105,0404
Non-polymers3,98218
Water1,45981
1
A: Glycoprotein 120
D: Antibody C8 VHH domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,51111
Polymers52,5202
Non-polymers1,9919
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4880 Å2
ΔGint12 kcal/mol
Surface area20430 Å2
MethodPISA
2
B: Antibody C8 VHH domain
C: Glycoprotein 120
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,51111
Polymers52,5202
Non-polymers1,9919
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5080 Å2
ΔGint14 kcal/mol
Surface area19990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.077, 87.403, 91.581
Angle α, β, γ (deg.)90.000, 109.120, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Glycoprotein 120


Mass: 39830.789 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: The extended core of HIV-1 gp120 from strain HXBc2 / Source: (gene. exp.) Human immunodeficiency virus 1 / Plasmid: pVRC8400 / Cell line (production host): HEK 293F / Production host: Homo sapiens (human)
#2: Antibody Antibody C8 VHH domain


Mass: 12689.152 Da / Num. of mol.: 2 / Fragment: VHH domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: pVRC8400 / Cell line (production host): 293F / Production host: Homo sapiens (human)
#3: 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.: 18 / Source method: obtained synthetically / 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.18 Å3/Da / Density % sol: 43.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 1.0 M Li2SO4 and 100 mM HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Oct 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 21712 / % possible obs: 94 % / Redundancy: 3.2 % / Biso Wilson estimate: 49.49 Å2 / Rmerge(I) obs: 0.139 / Χ2: 1.064 / Net I/σ(I): 8.6 / Num. measured all: 69593
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.75-2.81.70.3685721.185150.2
2.8-2.851.90.2987851.07168.1
2.85-2.920.3318951.023179.3
2.9-2.962.30.30310370.994188.7
2.96-3.032.50.29710771.042195.9
3.03-3.12.70.27211501.027198.6
3.1-3.172.90.28511221.086199.3
3.17-3.263.10.25111671.096199.8
3.26-3.363.30.24211521.097199.9
3.36-3.463.40.21911521.071100
3.46-3.593.60.20311391.063199.5
3.59-3.733.70.18211461.107199.9
3.73-3.93.70.16911601.106199.7
3.9-4.113.70.13811561.067199.7
4.11-4.363.70.12111601.091199.9
4.36-4.73.70.11511351.054199.8
4.7-5.173.70.09811491.019199.9
5.17-5.923.70.09711821.098199.8
5.92-7.463.70.09511751.047199.8
7.46-503.50.11212010.9781100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
PHENIX1.19-4092refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TMF

3tmf
PDB Unreleased entry


Resolution: 2.76→49.56 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 29.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2699 1103 5.09 %
Rwork0.2116 20581 -
obs0.2145 21684 93.16 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.11 Å2 / Biso mean: 51.3368 Å2 / Biso min: 18.55 Å2
Refinement stepCycle: final / Resolution: 2.76→49.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6426 0 252 81 6759
Biso mean--71.65 43.7 -
Num. residues----829
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.76-2.890.34910.29051576166758
2.89-3.040.36171270.26672418254589
3.04-3.230.35911440.24192749289399
3.23-3.480.31711360.237627542890100
3.48-3.830.27711690.199327302899100
3.83-4.380.25061400.17727742914100
4.38-5.520.2041450.176127622907100
5.52-49.560.24941510.227928182969100
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)
17.1616-1.0302-1.37110.05310.15041.80140.0722-0.45090.7794-0.03390.03-0.0445-0.2676-0.2769-0.10810.26390.04040.01620.4634-0.03020.4064-7.3691-42.64430.4373
22.8877-1.13130.31265.53681.03493.25810.14550.86130.2113-0.5882-0.13780.23560.0201-0.0498-0.02390.2554-0.0322-0.03670.64870.11110.3378-15.5268-42.43688.2056
32.346-0.2178-0.18120.7159-0.41341.76670.16580.51050.227-0.1833-0.00670.23670.0601-0.4071-0.0990.23630.0151-0.01830.38290.02770.3552-18.2259-43.510318.2898
43.28450.6257-0.2555.5633-1.22833.0534-0.0939-0.4561-0.10830.4540.2416-0.218-0.29360.0545-0.24960.1620.0974-0.0210.32840.03450.36266.9083-32.183130.5107
54.2739-0.611.47246.26970.75566.0453-0.31440.48030.3197-1.1624-0.01041.6166-0.56-0.96740.20170.37630.11410.03240.60450.07740.655462.281-31.097519.646
64.44081.3628-2.46434.2671-1.50714.0577-0.20490.4998-0.1169-0.65090.2433-0.57430.71950.06280.15310.209-0.03490.15850.57780.07340.425472.6898-34.363223.177
72.96781.8486-0.77295.50610.38840.39170.01360.02040.4644-0.06840.0173-0.3377-0.0984-0.2303-0.00070.2030.0453-0.03760.56020.0860.432361.7163-31.806626.6881
87.6103-0.40162.28440.02280.09092.13670.1714-0.9319-0.7423-0.1570.06220.02940.253-0.1064-0.18410.2904-0.04720.05480.38490.05430.415138.8219-45.77431.5949
94.4065-0.5748-1.46282.33520.09542.9810.05590.4638-0.0762-0.30490.04680.0246-0.01220.3191-0.06510.2383-0.0299-0.00730.5088-0.10690.30142.1828-44.253311.1188
103.2045-0.59311.13831.05270.25352.6259-0.00610.7587-0.2659-0.23820.03980.03610.07340.2888-0.00030.2579-0.01910.06950.3916-0.00570.38149.6915-45.895115.2967
114.07871.2933-1.24524.42770.36152.6845-0.0414-0.5876-0.46790.26180.05520.45240.33690.2878-0.11220.16760.0907-0.00630.39840.06640.4837-36.4615-56.040730.2972
120.3181-0.4458-0.93341.63760.90252.91570.30410.5881-0.09520.2009-0.08540.3792-0.2617-0.0711-0.23580.88810.39820.75481.1707-0.02881.4434-28.011-64.686117.2616
132.6625-1.62982.15499.55831.60453.1864-0.70150.72531.0068-0.63270.4577-1.1078-0.7280.48230.27830.4102-0.0367-0.00750.4242-0.06390.4715-37.9468-49.245719.3304
145.7541-0.38380.70846.67062.43694.3157-0.4079-0.1737-0.1922-0.51580.12340.9972-0.38320.15630.39750.2228-0.0150.02630.2736-0.00670.5296-43.4117-55.753624.8307
153.95073.1927-0.41425.6186-1.1421.39460.0008-0.4484-0.85550.0954-0.2459-0.13480.23630.5440.25610.24580.01520.15460.4277-0.080.3856-31.2416-56.260726.4639
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 45 through 258 )A45 - 258
2X-RAY DIFFRACTION2chain 'A' and (resid 259 through 413 )A259 - 413
3X-RAY DIFFRACTION3chain 'A' and (resid 414 through 491 )A414 - 491
4X-RAY DIFFRACTION4chain 'B' and (resid 1 through 39 )B1 - 39
5X-RAY DIFFRACTION5chain 'B' and (resid 40 through 52 )B40 - 52
6X-RAY DIFFRACTION6chain 'B' and (resid 53 through 90 )B53 - 90
7X-RAY DIFFRACTION7chain 'B' and (resid 91 through 118 )B91 - 118
8X-RAY DIFFRACTION8chain 'C' and (resid 45 through 235 )C45 - 235
9X-RAY DIFFRACTION9chain 'C' and (resid 236 through 377 )C236 - 377
10X-RAY DIFFRACTION10chain 'C' and (resid 378 through 491 )C378 - 491
11X-RAY DIFFRACTION11chain 'D' and (resid 1 through 39 )D1 - 39
12X-RAY DIFFRACTION12chain 'D' and (resid 40 through 45 )D40 - 45
13X-RAY DIFFRACTION13chain 'D' and (resid 46 through 63 )D46 - 63
14X-RAY DIFFRACTION14chain 'D' and (resid 64 through 90 )D64 - 90
15X-RAY DIFFRACTION15chain 'D' and (resid 91 through 118 )D91 - 118

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