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- PDB-6ncp: Crystal structure of HIV-1 broadly neutralizing antibody ACS202 -

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Basic information

Entry
Database: PDB / ID: 6ncp
TitleCrystal structure of HIV-1 broadly neutralizing antibody ACS202
Components
  • ACS202 Fab heavy chain
  • ACS202 Fab light chain
  • HIV-1 Fusion Peptide (residues 512-520)
  • His-tag of fusion peptide
KeywordsIMMUNE SYSTEM / antibody / HIV / envelope glycoprotein / fusion peptide
Function / homology
Function and homology information


Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / 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 ...Synthesis and processing of ENV and VPU / evasion of host immune response / Alpha-defensins / Dectin-2 family / Binding and entry of HIV virion / 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 / actin filament organization / Assembly Of The HIV Virion / Budding and maturation of HIV virion / clathrin-dependent endocytosis of virus by host cell / viral protein processing / symbiont entry into host cell / 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 / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
GLYCINE / Envelope glycoprotein gp160
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 Å
AuthorsYuan, M. / Wilson, I.A.
Funding support United States, 2items
OrganizationGrant numberCountry
International AIDS Vaccine Initiative United States
Bill & Melinda Gates Foundation United States
CitationJournal: Cell Host Microbe / Year: 2019
Title: Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies.
Authors: Meng Yuan / Christopher A Cottrell / Gabriel Ozorowski / Marit J van Gils / Sonu Kumar / Nicholas C Wu / Anita Sarkar / Jonathan L Torres / Natalia de Val / Jeffrey Copps / John P Moore / ...Authors: Meng Yuan / Christopher A Cottrell / Gabriel Ozorowski / Marit J van Gils / Sonu Kumar / Nicholas C Wu / Anita Sarkar / Jonathan L Torres / Natalia de Val / Jeffrey Copps / John P Moore / Rogier W Sanders / Andrew B Ward / Ian A Wilson /
Abstract: The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as ...The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "β strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
History
DepositionDec 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2019Group: Database references / Category: citation / citation_author
Item: _citation.page_last / _citation.pdbx_database_id_PubMed ..._citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: ACS202 Fab heavy chain
B: ACS202 Fab light chain
C: ACS202 Fab heavy chain
D: ACS202 Fab light chain
E: HIV-1 Fusion Peptide (residues 512-520)
F: His-tag of fusion peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,44910
Polymers99,0866
Non-polymers3634
Water1,08160
1
A: ACS202 Fab heavy chain
B: ACS202 Fab light chain
F: His-tag of fusion peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,6465
Polymers49,4743
Non-polymers1712
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: ACS202 Fab heavy chain
D: ACS202 Fab light chain
E: HIV-1 Fusion Peptide (residues 512-520)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,8045
Polymers49,6123
Non-polymers1922
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.444, 78.444, 340.854
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21(chain C and (resid 1 through 133 or resid 135 through 213))
12chain B
22chain D

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111GLNGLNPROPROchain AAA1 - 2131 - 232
211GLNGLNGLYGLY(chain C and (resid 1 through 133 or resid 135 through 213))CC1 - 1331 - 152
221THRTHRPROPRO(chain C and (resid 1 through 133 or resid 135 through 213))CC135 - 213154 - 232
112ALAALAGLYGLYchain BBB1 - 2121 - 212
212ALAALAGLYGLYchain DDD1 - 2121 - 212

NCS ensembles :
ID
1
2

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Components

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Protein/peptide , 2 types, 2 molecules EF

#3: Protein/peptide HIV-1 Fusion Peptide (residues 512-520)


Mass: 846.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: UniProt: P04578*PLUS
#4: Protein/peptide His-tag of fusion peptide


Mass: 708.749 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Antibody , 2 types, 4 molecules ACBD

#1: Antibody ACS202 Fab heavy chain


Mass: 25295.486 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody ACS202 Fab light chain


Mass: 23470.197 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Non-polymers , 3 types, 64 molecules

#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-GLY / GLYCINE / Glycine


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H5NO2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 3.06 Å3/Da / Density % sol: 59.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.7 / Details: 1.6 M ammonium sulfate, 0.1 M bicine, pH8.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.76→58.31 Å / Num. obs: 30474 / % possible obs: 100 % / Redundancy: 11.8 % / Biso Wilson estimate: 59.14 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.28 / Rpim(I) all: 0.09 / Net I/σ(I): 5.4
Reflection shellResolution: 2.76→2.81 Å / Redundancy: 11.8 % / Rmerge(I) obs: 1.54 / Num. unique obs: 1555 / CC1/2: 0.84 / Rpim(I) all: 0.47 / % possible all: 100

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.12_2829refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZYK

4zyk


Resolution: 2.76→58.3 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.9
RfactorNum. reflection% reflection
Rfree0.2563 1476 4.93 %
Rwork0.2219 --
obs0.2236 29909 98.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 141.39 Å2 / Biso mean: 64.8227 Å2 / Biso min: 20.18 Å2
Refinement stepCycle: final / Resolution: 2.76→58.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6836 0 20 60 6916
Biso mean--86.2 44.96 -
Num. residues----895
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047022
X-RAY DIFFRACTIONf_angle_d0.8449534
X-RAY DIFFRACTIONf_chiral_restr0.0541052
X-RAY DIFFRACTIONf_plane_restr0.0051221
X-RAY DIFFRACTIONf_dihedral_angle_d10.2044134
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A1962X-RAY DIFFRACTION13.281TORSIONAL
12C1962X-RAY DIFFRACTION13.281TORSIONAL
21B1875X-RAY DIFFRACTION13.281TORSIONAL
22D1875X-RAY DIFFRACTION13.281TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7592-2.84820.44781370.38292458259595
2.8482-2.950.33791190.35182538265796
2.95-3.06810.33431530.32582511266497
3.0681-3.20770.38371270.30682572269998
3.2077-3.37680.31191240.26862598272299
3.3768-3.58840.26341320.24252642277499
3.5884-3.86540.26561510.225825792730100
3.8654-4.25430.21271270.192526302757100
4.2543-4.86960.17341230.158126572780100
4.8696-6.13410.2361320.182926212753100
6.1341-58.31980.23011510.19426272778100
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)
13.9193-1.2153-1.43165.53812.2072.74490.1866-0.32550.1386-1.1977-0.22290.0059-0.2749-0.56360.18690.44470.06420.01240.5071-0.12210.376994.784468.5597-25.9707
25.8003-0.7021-2.68422.7560.21454.91210.41020.28070.1407-0.8114-0.09830.1372-0.6683-0.4729-0.20050.41560.0827-0.08920.5556-0.12070.498785.413164.2615-25.3639
31.29531.95860.4992.9840.46892.5237-0.09470.5365-0.0927-0.6496-0.51360.4887-0.6858-0.82650.37620.56660.2471-0.03660.8675-0.23850.447188.000869.7925-28.7472
41.2992-0.0759-0.09392.02940.66261.4555-0.07880.2182-0.1035-0.2712-0.0529-0.39270.1521-0.04170.13780.4806-0.01670.11240.5857-0.01750.396189.440263.8257-23.9877
57.7104-0.23821.60395.6042-0.6855.261-0.2730.75420.5655-0.09390.2482-0.5795-0.51830.84120.02940.3815-0.10290.03850.55710.02850.46199.490790.7609-4.3754
65.5511.56240.75854.94781.22386.117-0.11160.62340.0895-1.30250.1634-1.3199-0.37030.8941-0.0980.6704-0.12710.06430.89210.24570.7912105.181991.7243-11.6619
73.10412.49082.13144.74862.85992.1494-0.3151-0.265-0.37040.1368-0.10650.6803-0.9319-1.31490.47110.44310.16990.03870.6415-0.16010.517277.538463.9235-3.6161
83.20091.74312.0064.36763.80743.29430.0681-0.0067-0.87431.2124-0.53891.27491.3378-0.18530.27320.7270.17170.09580.71440.01340.397583.610459.60443.5118
93.86040.0724-1.37583.1478-0.07445.7346-0.19030.2047-0.4723-0.02890.0912-0.05940.38260.06390.05270.36380.0680.07550.3826-0.10420.40486.928856.5684-7.5283
104.1280.83562.25442.99421.8068.4336-0.33610.244-0.3527-0.07720.0949-0.207-0.1109-0.01290.18820.33640.13390.09440.5479-0.08810.518885.583963.3651-5.6179
112.4093-0.1676-0.08623.0212-2.5535.53990.31920.17970.47030.2394-0.5002-0.4636-0.5890.73130.17090.4789-0.0624-0.00140.52480.00080.55392.369193.25913.9216
122.9666-0.04720.81384.58470.17763.5507-0.08710.23180.7183-0.1947-0.0762-0.5074-0.75850.18320.10790.4897-0.0555-0.03680.44130.04820.518288.761597.17664.9362
132.8037-0.3094-1.52513.89160.71172.758-0.0866-0.30280.03560.4361-0.05580.0042-0.084-0.11710.13750.4010.0446-0.03370.3221-0.00260.361870.741764.399438.8714
141.29972.23990.99724.46440.59171.37270.0899-0.4461-0.1088-0.1988-0.3616-0.2196-0.2568-0.29670.32930.46840.0640.02430.4195-0.02140.327275.464869.264236.2602
154.1851-3.93232.99314.4171-3.13562.25030.8586-0.6957-0.71430.7741-0.95912.24970.9682-0.7619-0.29840.7778-0.03210.01990.676-0.16880.697172.48844.123942.1715
160.3393-0.5772-0.05041.5155-0.84181.57960.1822-0.13060.10190.0815-0.1965-0.3632-0.3078-0.4868-0.15380.35540.17650.06040.3761-0.04220.424669.155370.897633.5324
174.527-1.457-0.37871.2874-1.35122.6678-0.09060.00481.26560.18421.21080.8557-0.103-0.6176-0.59870.63420.3111-0.16590.99730.26031.215151.214295.874910.8956
182.4166-0.59531.27864.0013-0.63274.49730.0794-0.28170.14140.28110.12730.6506-0.4206-1.3423-0.19790.5450.21840.12130.8375-0.05720.512557.435986.530222.9018
193.3023-1.45210.76825.7169-3.45376.7359-0.2542-0.1162-0.3696-0.5178-0.054-0.82260.6817-0.22040.14870.39960.05580.06710.3512-0.10750.522280.391858.301313.8372
201.41130.12391.37642.4598-0.98615.96120.2048-0.1125-0.2303-0.0405-0.15130.07030.3288-0.4423-0.0710.3014-0.01890.01570.3416-0.07790.429472.234758.090817.7871
210.75440.51930.06436.55271.87135.5440.1176-0.07790.03390.2053-0.05740.3264-0.7634-0.7562-0.0090.52070.2826-0.01730.59310.02280.481264.415890.618210.8062
220.14440.1213-0.040.0981-0.03290.0062-1.27820.34390.07670.61311.1718-0.61950.3045-0.73-0.01471.1480.0973-0.24430.790.27881.000369.8008106.6966.8315
233.62883.42611.14147.58224.00243.9764-0.2624-0.01180.3627-0.13180.13210.7255-0.5546-0.2790.0160.50850.18530.02870.39960.05310.416168.029885.410111.9186
241.60390.8687-0.88790.55290.88563.12370.18020.12020.726-0.0362-0.0624-0.029-1.6479-0.32690.06481.07830.35770.04580.5230.01630.676164.7217101.84779.2894
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 1:38)A1 - 38
2X-RAY DIFFRACTION2(chain A and resid 39:59)A39 - 59
3X-RAY DIFFRACTION3(chain A and resid 60:95)A60 - 95
4X-RAY DIFFRACTION4(chain A and resid 96:120)A96 - 120
5X-RAY DIFFRACTION5(chain A and resid 121:192)A121 - 192
6X-RAY DIFFRACTION6(chain A and resid 193:213)A193 - 213
7X-RAY DIFFRACTION7(chain B and resid 1:14)B1 - 14
8X-RAY DIFFRACTION8(chain B and resid 15:24)B15 - 24
9X-RAY DIFFRACTION9(chain B and resid 25:74)B25 - 74
10X-RAY DIFFRACTION10(chain B and resid 75:107)B75 - 107
11X-RAY DIFFRACTION11(chain B and resid 108:147)B108 - 147
12X-RAY DIFFRACTION12(chain B and resid 148:212)B148 - 212
13X-RAY DIFFRACTION13(chain C and resid 1:80)C1 - 80
14X-RAY DIFFRACTION14(chain C and resid 81:96)C81 - 96
15X-RAY DIFFRACTION15(chain C and resid 97:100F)C97 - 100
16X-RAY DIFFRACTION16(chain C and resid 100G:123)C100
17X-RAY DIFFRACTION17(chain C and resid 124:133)C124 - 133
18X-RAY DIFFRACTION18(chain C and resid 134:213)C134 - 213
19X-RAY DIFFRACTION19(chain D and resid 1:31)D1 - 31
20X-RAY DIFFRACTION20(chain D and resid 32:104)D32 - 104
21X-RAY DIFFRACTION21(chain D and resid 105:148)D105 - 148
22X-RAY DIFFRACTION22(chain D and resid 149:154)D149 - 154
23X-RAY DIFFRACTION23(chain D and resid 155:178)D155 - 178
24X-RAY DIFFRACTION24(chain D and resid 179:212)D179 - 212

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