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- PDB-8vvk: CCHFV GP38 bound to ADI-46143 Fab -

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Basic information

Entry
Database: PDB / ID: 8vvk
TitleCCHFV GP38 bound to ADI-46143 Fab
Components
  • (ADI-46143 Fab ...) x 2
  • GP38
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / CCHFV / GP38 / Antibody / Immunology / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell Golgi membrane / clathrin-dependent endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / virion membrane / membrane
Similarity search - Function
Nairovirus M polyprotein-like / : / : / : / : / Nairovirus GP38 / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Hantavirus glycoprotein Gc ...Nairovirus M polyprotein-like / : / : / : / : / Nairovirus GP38 / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Hantavirus glycoprotein Gc / : / Hantavirus glycoprotein Gc, N-terminal / Hantavirus glycoprotein Gc, C-terminal
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesCrimean-Congo hemorrhagic fever virus
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsHjorth, C.K. / McLellan, J.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI152246 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19AI142777 United States
CitationJournal: Cell Rep / Year: 2024
Title: Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38.
Authors: Olivia S Shin / Stephanie R Monticelli / Christy K Hjorth / Vladlena Hornet / Michael Doyle / Dafna Abelson / Ana I Kuehne / Albert Wang / Russell R Bakken / Akaash K Mishra / Marissa ...Authors: Olivia S Shin / Stephanie R Monticelli / Christy K Hjorth / Vladlena Hornet / Michael Doyle / Dafna Abelson / Ana I Kuehne / Albert Wang / Russell R Bakken / Akaash K Mishra / Marissa Middlecamp / Elizabeth Champney / Lauran Stuart / Daniel P Maurer / Jiannan Li / Jacob Berrigan / Jennifer Barajas / Stephen Balinandi / Julius J Lutwama / Leslie Lobel / Larry Zeitlin / Laura M Walker / John M Dye / Kartik Chandran / Andrew S Herbert / Noel T Pauli / Jason S McLellan /
Abstract: Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of ...Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection. Competition experiments show that these antibodies bind across 5 distinct antigenic sites, encompassing 11 overlapping regions. Additionally, we show structures of GP38 bound with 9 of these antibodies targeting different antigenic sites. Although these GP38-specific antibodies are non-neutralizing, several display protective efficacy equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and may inform the development of broadly effective CCHFV antibody therapeutics.
History
DepositionJan 31, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: 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.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 30, 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: GP38
B: GP38
C: ADI-46143 Fab Light Chain
D: ADI-46143 Fab Heavy Chain
H: ADI-46143 Fab Heavy Chain
L: ADI-46143 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,74610
Polymers152,8866
Non-polymers1,8604
Water4,270237
1
A: GP38
H: ADI-46143 Fab Heavy Chain
L: ADI-46143 Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,2925
Polymers76,4433
Non-polymers8492
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: GP38
C: ADI-46143 Fab Light Chain
D: ADI-46143 Fab Heavy Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,4545
Polymers76,4433
Non-polymers1,0112
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)149.647, 149.647, 315.727
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6

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Components

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Antibody , 2 types, 4 molecules CLDH

#2: Antibody ADI-46143 Fab Light Chain


Mass: 22471.824 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody ADI-46143 Fab Heavy Chain


Mass: 23729.463 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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Protein / Non-polymers , 2 types, 239 molecules AB

#1: Protein GP38


Mass: 30241.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Crimean-Congo hemorrhagic fever virus / Strain: IbAr10200 / Gene: GP / Production host: Homo sapiens (human) / References: UniProt: Q8JSZ3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 237 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 4 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE

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Details

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: 3.34 Å3/Da / Density % sol: 63.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2 M Ammonium Citrate pH 7.5, 9.3% (w/v) PEG 3350, 12.6% (v/v) 2-Propanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 15, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.61→59.95 Å / Num. obs: 64162 / % possible obs: 99.93 % / Redundancy: 2 % / Biso Wilson estimate: 49.12 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.02675 / Rpim(I) all: 0.02675 / Rrim(I) all: 0.03784 / Net I/σ(I): 15.64
Reflection shellResolution: 2.61→2.703 Å / Redundancy: 2 % / Rmerge(I) obs: 0.262 / Mean I/σ(I) obs: 2.81 / Num. unique obs: 6283 / CC1/2: 0.814 / CC star: 0.947 / Rpim(I) all: 0.262 / Rrim(I) all: 0.3706 / % possible all: 99.86

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→59.95 Å / SU ML: 0.2805 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.3504
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2174 3178 4.94 %
Rwork0.1771 61163 -
obs0.1791 64162 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.33 Å2
Refinement stepCycle: LAST / Resolution: 2.61→59.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10294 0 123 237 10654
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.005410650
X-RAY DIFFRACTIONf_angle_d0.74114468
X-RAY DIFFRACTIONf_chiral_restr0.04941669
X-RAY DIFFRACTIONf_plane_restr0.00561823
X-RAY DIFFRACTIONf_dihedral_angle_d5.60861496
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.61-2.650.32451280.25252611X-RAY DIFFRACTION100
2.65-2.690.31991450.24492595X-RAY DIFFRACTION99.85
2.69-2.730.31181540.23342587X-RAY DIFFRACTION99.82
2.73-2.780.28861350.23282621X-RAY DIFFRACTION99.86
2.78-2.830.29031380.22542598X-RAY DIFFRACTION99.96
2.83-2.880.30581150.21252644X-RAY DIFFRACTION99.93
2.88-2.940.28041490.22242593X-RAY DIFFRACTION99.96
2.94-3.010.30541290.21942635X-RAY DIFFRACTION99.89
3.01-3.080.27621250.21542621X-RAY DIFFRACTION100
3.08-3.150.25381290.20672632X-RAY DIFFRACTION99.96
3.15-3.240.27521350.19892644X-RAY DIFFRACTION100
3.24-3.330.21771250.20012646X-RAY DIFFRACTION100
3.33-3.440.26021530.19472609X-RAY DIFFRACTION100
3.44-3.560.22271480.18622667X-RAY DIFFRACTION100
3.56-3.710.24051330.17882632X-RAY DIFFRACTION100
3.71-3.880.18511270.17392653X-RAY DIFFRACTION99.93
3.88-4.080.19611320.15592681X-RAY DIFFRACTION100
4.08-4.340.19311540.14332648X-RAY DIFFRACTION100
4.34-4.670.15011270.12642713X-RAY DIFFRACTION99.96
4.67-5.140.15151600.13472680X-RAY DIFFRACTION100
5.14-5.880.19791360.1482733X-RAY DIFFRACTION100
5.88-7.410.1941620.18452755X-RAY DIFFRACTION100
7.41-59.950.19511390.17692965X-RAY DIFFRACTION99.68
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)
14.09232722664-1.317688567941.541870023395.3939019466-2.769639727973.63685725039-0.0305496103961-0.2631303967570.2120335186770.2420050897860.1643298016060.526848344349-0.186045165252-0.526260496325-0.130550960070.270502367278-0.02441480911170.002301104537840.5283970865260.02183067235010.375824398413-130.91679532.702923805912.716117711
24.170596669-0.297890814855-0.9115472746532.943055564031.039804096034.99636138180.06400080467390.02769641051440.2792219932880.0339103286993-0.09070815663280.0272673907096-0.2818482804330.002879295091070.02866529630420.276814105059-0.00376747652107-0.001668306873530.2859969193320.01410322269780.188045486047-94.23570405638.570926305214.6485896363
33.305810091141.080125606630.2657744549925.902762495851.045495791333.28517645338-0.270801559461-0.2839215414960.2756924395150.4131081096870.3766054791520.2787462293590.0262025423261-0.549046681654-0.1019586219620.356362161540.1381493243230.02287476684060.6351859358050.01004349277350.380331233597-130.80481853336.631601357928.5197618764
48.19269958421-2.03334498327-0.8785006298084.443377544460.2490334616813.912681858320.3753984118120.2992696536430.0115775908125-0.473872347654-0.35557207780.221619226289-0.6230730582250.08937185496140.002401118220.633216899654-0.0293289388183-0.04626324560050.312583688111-0.02276542715790.364362310694-23.338007085296.701846359134.8346176984
55.62500996669-1.735923786311.823572953551.37276993335-0.3416229512942.542482168160.2173929294680.9792221329360.0819616492111-0.128630825497-0.163644895269-0.3638099756790.03270225225880.702480386451-0.052201874370.4299371452260.01665676780080.04268361415540.61259191743-0.03707276380540.399574787162-56.783028625121.6255647140.642807034058
62.769693791591.354726982731.472943391984.243118669332.212841149874.206201452980.339182198492-0.0952874950937-0.4857236885810.27255351651-0.148472645555-0.1211443805060.70788655733-0.300443135562-0.1819103522580.472829966032-0.0643835434796-0.07486246387580.3813176970150.03868232523520.416744532993-43.327118195218.299230494735.4383123534
73.93210178321-0.7605664479350.4687280474565.82969069436-0.567892998812.4709343399-0.0445990708933-0.06384698841170.2387408231140.1458630949550.02769314568430.582658634844-0.118803160949-0.2129627943250.001815707664990.250545182393-0.02836988267390.006280631741740.3312129465810.04233028002740.313795844515-41.309740089662.418720080139.3406391961
82.778191200991.2466962041-0.4619731921253.072043552-1.604068682422.459330371630.04678814541570.152621797192-0.09225202945270.008478838561060.0549131056704-0.1104241011610.05916036858490.0654511596521-0.05201582092890.306407403599-0.0224426099846-0.03811110906230.311365461646-0.07328125817090.276700779767-20.10059388956.936540640442.2015411936
93.07770208278-2.97653305294-3.132244622586.504823909965.034556058447.453075125630.0478359021046-0.1313374057840.20516197330.1137537258930.1186371550360.0847810960278-0.3143529804530.209498069452-0.1625940799290.30810174183-0.119129454756-0.002143616503130.3533257280390.02786120819650.306867616051-17.034506492388.400254758747.1204193866
105.280737799361.80979604154-1.395022841872.52500839996-0.6989745382863.04519005163-7.10231444728E-50.288118533802-0.518754125372-0.162497946097-0.0350962286408-0.05518111851750.322686420925-0.07137940428210.04828965902890.3322307114180.0433904585806-0.06790485520710.285152872671-0.05569642598940.309728699456-101.95494543320.29780002245.08578546832
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'H' and resid 114 through 214)HN114 - 214124 - 224
22(chain 'L' and resid 1 through 106A)LO1 - 1061 - 108
33(chain 'L' and resid 107 through 208)LO107 - 208109 - 210
44(chain 'C' and resid 109 through 208)CL109 - 208111 - 210
55(chain 'A' and resid 253 through 512)AA253 - 5121 - 240
66(chain 'B' and resid 253 through 515)BF253 - 5151 - 240
77(chain 'C' and resid 1 through 108)CL1 - 1081 - 110
88(chain 'D' and resid 1 through 113)DM1 - 1131 - 123
99(chain 'D' and resid 114 through 213)DM114 - 213124 - 223
1010(chain 'H' and resid 1 through 113)HN1 - 1131 - 123

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