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- PDB-5niv: Crystal structure of 5D3 Fab -

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Basic information

Entry
Database: PDB / ID: 5niv
TitleCrystal structure of 5D3 Fab
Components
  • Heavy chain of 5D3 Fab
  • Light chain of 5D3 Fab
KeywordsIMMUNE SYSTEM / Fab / ABCG2 / inhibitor
Function / homologyImmunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Function and homology information
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.498 Å
AuthorsManolaridis, I. / Locher, K.P.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Swiss National Science FoundationNCCR TransCure Switzerland
ETH research grantETH-22-14-1 Switzerland
CitationJournal: Nature / Year: 2017
Title: Structure of the human multidrug transporter ABCG2.
Authors: Nicholas M I Taylor / Ioannis Manolaridis / Scott M Jackson / Julia Kowal / Henning Stahlberg / Kaspar P Locher /
Abstract: ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs ...ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance. Here we present the structure of human ABCG2 determined by cryo-electron microscopy, providing the first high-resolution insight into a human multidrug transporter. We visualize ABCG2 in complex with two antigen-binding fragments of the human-specific, inhibitory antibody 5D3 that recognizes extracellular loops of the transporter. We observe two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between the transmembrane domains. Combined with functional in vitro analyses, our results suggest a multidrug recognition and transport mechanism of ABCG2, rationalize disease-causing single nucleotide polymorphisms and the allosteric inhibition by the 5D3 antibody, and provide the structural basis of cholesterol recognition by other G-subfamily ABC transporters.
History
DepositionMar 27, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 28, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.0Jan 17, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_site.occupancy / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Light chain of 5D3 Fab
B: Heavy chain of 5D3 Fab


Theoretical massNumber of molelcules
Total (without water)47,2192
Polymers47,2192
Non-polymers00
Water10,359575
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-25 kcal/mol
Surface area18970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.203, 45.193, 83.278
Angle α, β, γ (deg.)90.00, 122.14, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-321-

HOH

21B-569-

HOH

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Components

#1: Antibody Light chain of 5D3 Fab


Mass: 23375.785 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#2: Antibody Heavy chain of 5D3 Fab


Mass: 23843.633 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 575 / 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: 2.39 Å3/Da / Density % sol: 48.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 100 mM Tris pH 8.5 and 16% PEG 6000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 30, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.498→42.197 Å / Num. obs: 66575 / % possible obs: 94.1 % / Redundancy: 7 % / Rmerge(I) obs: 0.073 / Net I/σ(I): 16.9
Reflection shellResolution: 1.5→1.55 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.566 / Mean I/σ(I) obs: 4.2 / Num. unique all: 6208 / % possible all: 88.2

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CAD

4cad


Resolution: 1.498→42.197 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.16 / Phase error: 20.26
RfactorNum. reflection% reflection
Rfree0.2053 6452 4.99 %
Rwork0.1807 --
obs0.1819 66575 93.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.498→42.197 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3273 0 0 575 3848
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063361
X-RAY DIFFRACTIONf_angle_d0.9954586
X-RAY DIFFRACTIONf_dihedral_angle_d15.51202
X-RAY DIFFRACTIONf_chiral_restr0.088517
X-RAY DIFFRACTIONf_plane_restr0.009578
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.498-1.51550.3911863486X-RAY DIFFRACTION79
1.5155-1.53330.32522073979X-RAY DIFFRACTION91
1.5333-1.5520.27622100.26653969X-RAY DIFFRACTION91
1.552-1.57170.31162100.26833958X-RAY DIFFRACTION92
1.5717-1.59240.27312110.24794011X-RAY DIFFRACTION91
1.5924-1.61420.26442130.2394072X-RAY DIFFRACTION93
1.6142-1.63730.23042140.21154083X-RAY DIFFRACTION93
1.6373-1.66170.21822170.19044107X-RAY DIFFRACTION94
1.6617-1.68770.2142150.19544044X-RAY DIFFRACTION94
1.6877-1.71530.25192180.18834155X-RAY DIFFRACTION95
1.7153-1.74490.21532190.17764233X-RAY DIFFRACTION95
1.7449-1.77660.20862110.18524089X-RAY DIFFRACTION95
1.7766-1.81080.22752230.1824246X-RAY DIFFRACTION96
1.8108-1.84780.20442160.17494107X-RAY DIFFRACTION96
1.8478-1.88790.1982190.1794203X-RAY DIFFRACTION95
1.8879-1.93190.23262160.1754115X-RAY DIFFRACTION95
1.9319-1.98020.21182100.17464063X-RAY DIFFRACTION92
1.9802-2.03370.19651850.17293598X-RAY DIFFRACTION83
2.0337-2.09360.1752210.16484231X-RAY DIFFRACTION97
2.0936-2.16110.17442270.17114297X-RAY DIFFRACTION97
2.1611-2.23840.23342250.17824208X-RAY DIFFRACTION97
2.2384-2.3280.20012200.17824220X-RAY DIFFRACTION97
2.328-2.43390.19262280.18294292X-RAY DIFFRACTION97
2.4339-2.56220.24642180.18614220X-RAY DIFFRACTION97
2.5622-2.72270.22532270.18254263X-RAY DIFFRACTION97
2.7227-2.93290.22222210.18434229X-RAY DIFFRACTION97
2.9329-3.2280.19692170.17484203X-RAY DIFFRACTION95
3.228-3.69480.17672010.16983748X-RAY DIFFRACTION86
3.6948-4.65410.1592250.14914124X-RAY DIFFRACTION94
4.6541-42.1970.18762220.17034316X-RAY DIFFRACTION98

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