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- PDB-8aed: Broadly neutralizing DARPin bnD.9 in complex with the HIV-1 envel... -

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Basic information

Entry
Database: PDB / ID: 8aed
TitleBroadly neutralizing DARPin bnD.9 in complex with the HIV-1 envelope variable loop 3 peptide V3 (BG505)
Components
  • Broadly neutralizing DARPin bnD.9
  • Envelope glycoprotein gp160
KeywordsDE NOVO PROTEIN / DARPin / HIV
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 / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / 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 / host cell endosome membrane / clathrin-dependent endocytosis of virus by host cell / viral protein processing / fusion of virus membrane with host plasma membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / structural molecule activity / virion membrane / 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
ACETATE ION / CITRIC ACID / Envelope glycoprotein gp160
Similarity search - Component
Biological speciessynthetic construct (others)
Human immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.17 Å
AuthorsMittl, P. / Gloegl, M.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation Switzerland
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.
Authors: Matthias Glögl / Nikolas Friedrich / Gabriele Cerutti / Thomas Lemmin / Young D Kwon / Jason Gorman / Liridona Maliqi / Peer R E Mittl / Maria C Hesselman / Daniel Schmidt / Jacqueline ...Authors: Matthias Glögl / Nikolas Friedrich / Gabriele Cerutti / Thomas Lemmin / Young D Kwon / Jason Gorman / Liridona Maliqi / Peer R E Mittl / Maria C Hesselman / Daniel Schmidt / Jacqueline Weber / Caio Foulkes / Adam S Dingens / Tatsiana Bylund / Adam S Olia / Raffaello Verardi / Thomas Reinberg / Nicolas S Baumann / Peter Rusert / Birgit Dreier / Lawrence Shapiro / Peter D Kwong / Andreas Plückthun / Alexandra Trkola /
Abstract: The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows ...The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.
History
DepositionJul 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 23, 2023Group: 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Aug 30, 2023Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Sep 20, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Broadly neutralizing DARPin bnD.9
B: Broadly neutralizing DARPin bnD.9
C: Envelope glycoprotein gp160
D: Envelope glycoprotein gp160
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,38015
Polymers39,5574
Non-polymers82411
Water8,881493
1
A: Broadly neutralizing DARPin bnD.9
C: Envelope glycoprotein gp160
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2619
Polymers19,7782
Non-polymers4837
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2360 Å2
ΔGint-20 kcal/mol
Surface area8580 Å2
MethodPISA
2
B: Broadly neutralizing DARPin bnD.9
D: Envelope glycoprotein gp160
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1196
Polymers19,7782
Non-polymers3414
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2250 Å2
ΔGint-19 kcal/mol
Surface area8560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.795, 55.233, 58.032
Angle α, β, γ (deg.)90.000, 98.540, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein Broadly neutralizing DARPin bnD.9


Mass: 17211.521 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Protein/peptide Envelope glycoprotein gp160 / Env polyprotein


Mass: 2566.889 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Human immunodeficiency virus 1 / References: UniProt: Q9Q714

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Non-polymers , 5 types, 504 molecules

#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H8O7
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 493 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.04 Å3/Da / Density % sol: 39.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM trisodium citrate, pH 4.31 165 mM magnesium acetate 20% PEG smear broad (PSB)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 12M / Detector: PIXEL / Date: Nov 25, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.17→57.39 Å / Num. obs: 79970 / % possible obs: 87.5 % / Redundancy: 6.2 % / Biso Wilson estimate: 10.56 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.046 / Rrim(I) all: 0.085 / Net I/σ(I): 12.3
Reflection shellResolution: 1.17→1.25 Å / Mean I/σ(I) obs: 1.8 / Num. unique obs: 3995 / CC1/2: 0.635 / % possible all: 43.1

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2QYJ

2qyj


Resolution: 1.17→50.23 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 20.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1839 3993 4.99 %
Rwork0.1541 75973 -
obs0.1556 79966 74.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 69.1 Å2 / Biso mean: 15.9323 Å2 / Biso min: 5.25 Å2
Refinement stepCycle: final / Resolution: 1.17→50.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2716 0 93 493 3302
Biso mean--22.49 29.43 -
Num. residues----362
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 29

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.17-1.180.2761270.255345348013
1.18-1.190.3058250.222554857316
1.19-1.210.2356340.219764968318
1.21-1.230.3312360.216578782322
1.23-1.240.2726500.204793298227
1.24-1.260.2422640.20671112117632
1.26-1.280.2836740.19991365143939
1.28-1.30.2761900.19571670176047
1.3-1.320.24921090.18772139224861
1.32-1.340.21641220.1772411253368
1.34-1.370.21391400.17212645278576
1.37-1.390.23721530.16712923307683
1.39-1.420.21971720.16343193336591
1.42-1.450.19131780.16373369354795
1.45-1.490.1781760.15093337351396
1.49-1.520.17421780.14653384356296
1.52-1.570.16991780.14333381355996
1.57-1.610.18481780.14223389356796
1.61-1.660.16671810.1483427360896
1.66-1.720.17551790.14573392357197
1.72-1.790.19891820.14383432361497
1.79-1.870.18151800.15043470365097
1.87-1.970.19661810.14553431361298
1.97-2.10.16771810.13653471365298
2.1-2.260.15691820.14113477365998
2.26-2.490.16981820.14313502368498
2.49-2.840.17421850.14713529371499
2.85-3.580.15811860.15323540372699
3.58-50.230.2011900.17023615380599

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