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- PDB-6axk: Crystal structure of Fab311 complex -

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Basic information

Entry
Database: PDB / ID: 6axk
TitleCrystal structure of Fab311 complex
Components
  • ACE-ASN-PRO-ASN-ALA-ASN-PRO-ASN-ALA-ASN-PRO-ASN
  • Fab311 heavy chain
  • Fab311 light chain
KeywordsIMMUNE SYSTEM / Fab fragment
Function / homology
Function and homology information


entry into host cell by a symbiont-containing vacuole / side of membrane / cell surface / plasma membrane / cytoplasm
Similarity search - Function
Plasmodium circumsporozoite protein / Thrombospondin type 1 domain / Thrombospondin type-1 (TSP1) repeat superfamily / Thrombospondin type-1 (TSP1) repeat profile. / Thrombospondin type 1 repeats / Thrombospondin type-1 (TSP1) repeat / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Circumsporozoite protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Plasmodium falciparum (malaria parasite P. falciparum)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.103 Å
AuthorsOyen, D. / Wilson, I.A.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2017
Title: Structural basis for antibody recognition of the NANP repeats in circumsporozoite protein.
Authors: David Oyen / Jonathan L Torres / Ulrike Wille-Reece / Christian F Ockenhouse / Daniel Emerling / Jacob Glanville / Wayne Volkmuth / Yevel Flores-Garcia / Fidel Zavala / Andrew B Ward / C ...Authors: David Oyen / Jonathan L Torres / Ulrike Wille-Reece / Christian F Ockenhouse / Daniel Emerling / Jacob Glanville / Wayne Volkmuth / Yevel Flores-Garcia / Fidel Zavala / Andrew B Ward / C Richter King / Ian A Wilson /
Abstract: Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)- ...Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA) peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I β-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of CSP, we used negative-stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP-Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next-generation malaria vaccine.
History
DepositionSep 7, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 22, 2017Provider: repository / Type: Initial release
Revision 2.0Dec 6, 2017Group: Atomic model / Database references / Category: atom_site / citation / citation_author
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _citation.journal_abbrev / _citation.pdbx_database_id_PubMed
Revision 2.1Dec 13, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 3.0Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Polymer sequence / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / entity_poly / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_poly.pdbx_seq_one_letter_code_can

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fab311 heavy chain
B: Fab311 light chain
E: ACE-ASN-PRO-ASN-ALA-ASN-PRO-ASN-ALA-ASN-PRO-ASN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,2228
Polymers48,1593
Non-polymers1,0625
Water4,360242
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6550 Å2
ΔGint-16 kcal/mol
Surface area19830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.117, 44.729, 186.079
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Detailstrimer by isothermal titration calorimetry

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Components

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Protein/peptide , 1 types, 1 molecules E

#3: Protein/peptide ACE-ASN-PRO-ASN-ALA-ASN-PRO-ASN-ALA-ASN-PRO-ASN


Mass: 1231.255 Da / Num. of mol.: 1 / Source method: obtained synthetically
Source: (synth.) Plasmodium falciparum (malaria parasite P. falciparum)
References: UniProt: P02893*PLUS

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Antibody , 2 types, 2 molecules AB

#1: Antibody Fab311 heavy chain


Mass: 23965.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody Fab311 light chain


Mass: 22962.469 Da / Num. of mol.: 1
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, 247 molecules

#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 2.86 Å3/Da / Density % sol: 56.94 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 0.1M MES pH6.0 36% PEG400 5% PEG3000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.1→46.52 Å / Num. obs: 32026 / % possible obs: 98.1 % / Redundancy: 5.1 % / CC1/2: 0.821 / Rpim(I) all: 0.077 / Rsym value: 0.174 / Net I/σ(I): 11
Reflection shellResolution: 2.1→2.14 Å / CC1/2: 0.465 / Rpim(I) all: 0.5 / Rsym value: 0.921

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: homology model

Resolution: 2.103→46.52 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.79
RfactorNum. reflection% reflection
Rfree0.2356 1606 5.02 %
Rwork0.2036 --
obs0.2053 31966 96.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.103→46.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3344 0 53 242 3639
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023496
X-RAY DIFFRACTIONf_angle_d0.6634775
X-RAY DIFFRACTIONf_dihedral_angle_d18.5212072
X-RAY DIFFRACTIONf_chiral_restr0.044524
X-RAY DIFFRACTIONf_plane_restr0.004610
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1031-2.17090.36641110.31032324X-RAY DIFFRACTION83
2.1709-2.24850.29891450.26872702X-RAY DIFFRACTION96
2.2485-2.33860.3171430.25172709X-RAY DIFFRACTION97
2.3386-2.4450.27011470.24462745X-RAY DIFFRACTION97
2.445-2.57390.31361420.23462792X-RAY DIFFRACTION99
2.5739-2.73510.2521450.22542779X-RAY DIFFRACTION98
2.7351-2.94630.25461590.22732799X-RAY DIFFRACTION99
2.9463-3.24270.23631320.22162797X-RAY DIFFRACTION98
3.2427-3.71180.20871550.18862809X-RAY DIFFRACTION98
3.7118-4.67570.19961630.15652872X-RAY DIFFRACTION99
4.6757-46.53110.20681640.17583032X-RAY DIFFRACTION99
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)
11.81780.3345-0.28771.89890.72242.41970.0637-0.25140.15970.1189-0.22260.46490.1049-0.43530.14660.2227-0.03230.02580.3077-0.07890.3662-17.766919.7255-38.2482
21.0523-0.8449-0.62431.39270.94913.765-0.04330.23540.0123-0.0080.0079-0.0916-0.1421-0.06970.06330.2189-0.006100.286-0.04330.3013-14.67437.8212-3.3909
37.9741-0.29471.83544.30511.66154.4977-0.26020.08530.41070.0952-0.1645-0.0312-0.3971-0.01590.25360.24580.02940.01210.2045-0.01910.286-19.422642.63043.9484
40.21570.11580.7616.7481.36686.18990.4121-0.4240.2020.9523-0.52010.16940.1794-0.29320.05110.21250.0457-0.05820.22260.02020.15545.984623.0692-24.1188
52.63080.93820.49452.63070.20942.47580.072-0.1684-0.08030.115-0.1248-0.22550.23430.10240.05070.23310.00540.00350.18470.0190.18893.845420.6951-33.9866
60.18210.09230.48470.5131.72322.2468-0.10030.0021-0.05240.0754-0.00820.11330.3310.0557-0.02040.3382-0.04280.02060.23110.00580.293-1.531621.7735-22.0663
74.68760.8878-2.66251.3466-0.98843.75820.10310.40390.02540.02750.02840.2538-0.0278-0.35470.05570.2417-0.02430.00740.225-0.05620.2402-9.326927.7341-2.6969
84.74350.7387-1.64692.2316-0.78233.5325-0.16490.2184-0.3987-0.04560.00430.10790.2672-0.06820.16260.2488-0.00560.00790.2174-0.09780.2673-6.17224.8282-4.2474
99.8765-2.77274.30794.43471.22833.53030.01630.52640.4089-0.4784-0.5654-0.32-0.40041.02040.65720.350.02520.02590.3012-0.01020.3134-8.65969.8095-47.2254
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 109 )
2X-RAY DIFFRACTION2chain 'A' and (resid 110 through 188 )
3X-RAY DIFFRACTION3chain 'A' and (resid 189 through 215 )
4X-RAY DIFFRACTION4chain 'B' and (resid 2 through 18 )
5X-RAY DIFFRACTION5chain 'B' and (resid 19 through 89 )
6X-RAY DIFFRACTION6chain 'B' and (resid 90 through 118 )
7X-RAY DIFFRACTION7chain 'B' and (resid 119 through 150 )
8X-RAY DIFFRACTION8chain 'B' and (resid 151 through 209 )
9X-RAY DIFFRACTION9chain 'E' and (resid 2 through 12 )

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