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Basic information

Entry
Database: PDB / ID: 6w3h
TitleBrain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys
Components
  • ATV Fc
  • Transferrin receptor protein 1,Transferrin receptor protein 1
KeywordsPROTEIN TRANSPORT / Blood-Brain Barrier / Transferrin binding receptor / Antibody transport vehicle
Function / homology
Function and homology information


transferrin receptor activity / negative regulation of mitochondrial fusion / transferrin transport / Transferrin endocytosis and recycling / positive regulation of isotype switching / response to copper ion / response to iron ion / response to manganese ion / RND1 GTPase cycle / RND2 GTPase cycle ...transferrin receptor activity / negative regulation of mitochondrial fusion / transferrin transport / Transferrin endocytosis and recycling / positive regulation of isotype switching / response to copper ion / response to iron ion / response to manganese ion / RND1 GTPase cycle / RND2 GTPase cycle / RHOB GTPase cycle / Golgi Associated Vesicle Biogenesis / RHOJ GTPase cycle / RHOC GTPase cycle / RHOQ GTPase cycle / CDC42 GTPase cycle / RHOH GTPase cycle / transport across blood-brain barrier / RHOG GTPase cycle / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / positive regulation of bone resorption / response to retinoic acid / positive regulation of T cell proliferation / clathrin-coated pit / positive regulation of B cell proliferation / Hsp70 protein binding / RAC1 GTPase cycle / response to nutrient / osteoclast differentiation / cellular response to leukemia inhibitory factor / acute-phase response / clathrin-coated endocytic vesicle membrane / positive regulation of protein-containing complex assembly / HFE-transferrin receptor complex / receptor internalization / recycling endosome / positive regulation of protein localization to nucleus / recycling endosome membrane / double-stranded RNA binding / extracellular vesicle / melanosome / cellular response to xenobiotic stimulus / Cargo recognition for clathrin-mediated endocytosis / positive regulation of peptidyl-serine phosphorylation / Clathrin-mediated endocytosis / virus receptor activity / positive regulation of NF-kappaB transcription factor activity / iron ion transport / cytoplasmic vesicle / basolateral plasma membrane / positive regulation of canonical NF-kappaB signal transduction / intracellular iron ion homeostasis / early endosome / blood microparticle / endosome membrane / response to hypoxia / intracellular signal transduction / endosome / positive regulation of protein phosphorylation / external side of plasma membrane / intracellular membrane-bounded organelle / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / cell surface / protein homodimerization activity / RNA binding / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane
Similarity search - Function
Transferrin receptor protein 1/2, PA domain / Transferrin receptor-like, dimerisation domain / Transferrin receptor-like, dimerisation domain superfamily / Glutamate carboxypeptidase 2-like / Transferrin receptor-like dimerisation domain / PA domain superfamily / PA domain / PA domain / Peptidase M28 / Peptidase family M28 ...Transferrin receptor protein 1/2, PA domain / Transferrin receptor-like, dimerisation domain / Transferrin receptor-like, dimerisation domain superfamily / Glutamate carboxypeptidase 2-like / Transferrin receptor-like dimerisation domain / PA domain superfamily / PA domain / PA domain / Peptidase M28 / Peptidase family M28 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Transferrin receptor protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.38 Å
AuthorsSrivastava, A. / Kariolis, M. / Wells, R.
CitationJournal: Sci Transl Med / Year: 2020
Title: Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys.
Authors: Kariolis, M.S. / Wells, R.C. / Getz, J.A. / Kwan, W. / Mahon, C.S. / Tong, R. / Kim, D.J. / Srivastava, A. / Bedard, C. / Henne, K.R. / Giese, T. / Assimon, V.A. / Chen, X. / Zhang, Y. / ...Authors: Kariolis, M.S. / Wells, R.C. / Getz, J.A. / Kwan, W. / Mahon, C.S. / Tong, R. / Kim, D.J. / Srivastava, A. / Bedard, C. / Henne, K.R. / Giese, T. / Assimon, V.A. / Chen, X. / Zhang, Y. / Solanoy, H. / Jenkins, K. / Sanchez, P.E. / Kane, L. / Miyamoto, T. / Chew, K.S. / Pizzo, M.E. / Liang, N. / Calvert, M.E.K. / DeVos, S.L. / Baskaran, S. / Hall, S. / Sweeney, Z.K. / Thorne, R.G. / Watts, R.J. / Dennis, M.S. / Silverman, A.P. / Zuchero, Y.J.Y.
History
DepositionMar 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.type_symbol / _chem_comp.name / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 18, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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: ATV Fc
C: Transferrin receptor protein 1,Transferrin receptor protein 1
D: Transferrin receptor protein 1,Transferrin receptor protein 1
B: ATV Fc
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,3815
Polymers87,0644
Non-polymers1,3171
Water00
1
A: ATV Fc
D: Transferrin receptor protein 1,Transferrin receptor protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,8493
Polymers43,5322
Non-polymers1,3171
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Transferrin receptor protein 1,Transferrin receptor protein 1
B: ATV Fc


Theoretical massNumber of molelcules
Total (without water)43,5322
Polymers43,5322
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)126.370, 126.370, 113.800
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12C
22D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERLEULEUAA239 - 44319 - 223
21SERSERLEULEUBD239 - 44319 - 223
12PROPROTHRTHRCB26 - 1686 - 148
22PROPROTHRTHRDC26 - 1686 - 148

NCS ensembles :
ID
1
2

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Components

#1: Protein ATV Fc


Mass: 25578.848 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: Protein Transferrin receptor protein 1,Transferrin receptor protein 1 / Trfr / T9 / p90


Mass: 17953.268 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TFRC / Production host: Homo sapiens (human) / References: UniProt: P02786
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[2-acetamido-2-deoxy-beta-D-glucopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1317.209 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-2DManpa1-3[DGlcpNAcb1-2DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-1-3-1/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1_f2-g1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][b-D-GlcpNAc]{}}[(6+1)][a-D-Manp]{[(2+1)][b-D-GlcpNAc]{}}}}}}LINUCSPDB-CARE
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: 3.01 Å3/Da / Density % sol: 59.17 %
Crystal growTemperature: 297.15 K / Method: vapor diffusion, sitting drop
Details: 20-25% PEG3350, 0.1M Bis-Tris pH6.5, and 0.2M LiSO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS3 100K-M / Detector: PIXEL / Date: Jul 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 3.38→55.3 Å / Num. obs: 14541 / % possible obs: 99.72 % / Redundancy: 9.5 % / CC1/2: 0.93 / Net I/σ(I): 7.2
Reflection shellResolution: 3.38→3.44 Å / Num. unique obs: 713 / CC1/2: 0.56

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3S7G

3s7g


Resolution: 3.38→55.3 Å / Cor.coef. Fo:Fc: 0.891 / Cor.coef. Fo:Fc free: 0.806 / SU B: 84.188 / SU ML: 0.621 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.673
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.3182 657 4.5 %RANDOM
Rwork0.2376 ---
obs0.2415 13862 99.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 151.16 Å2 / Biso mean: 72.05 Å2 / Biso min: 48.58 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0.23 Å2-0 Å2
2---0.45 Å20 Å2
3---1.47 Å2
Refinement stepCycle: final / Resolution: 3.38→55.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5162 0 89 0 5251
Biso mean--87.64 --
Num. residues----689
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0135381
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174769
X-RAY DIFFRACTIONr_angle_refined_deg1.771.677368
X-RAY DIFFRACTIONr_angle_other_deg1.5611.59411076
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2135681
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.60523.963217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.21415787
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5731514
X-RAY DIFFRACTIONr_chiral_restr0.0950.2765
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025951
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021048
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.15 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A5135
12B5135
21C3547
22D3547
LS refinement shellResolution: 3.38→3.468 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.417 40 -
Rwork0.292 1037 -
all-1077 -
obs--99.45 %
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)
11.9247-0.31810.51970.5075-0.04520.14410.05150.6130.0683-0.0673-0.0644-0.14090.00710.16880.01290.3404-0.03840.02220.4950.04370.237538.0099.318920.54
20.3874-0.07640.61192.14710.03422.1663-0.1648-0.08220.05860.15850.10520.1664-0.1787-0.03540.05960.34740.06050.03480.1427-0.02650.15225.101448.364919.089
30.52950.87130.18831.44810.15022.25140.0335-0.07110.04660.0525-0.12950.05040.1161-0.03850.0960.19210.0324-0.06780.2567-0.00110.228620.0765-23.3259.4291
40.7728-0.1414-0.46491.0353-0.30120.4595-0.01410.14940.16880.0771-0.0399-0.38990.0245-0.15920.0540.2308-0.0007-0.03220.2689-0.02680.294630.213225.65463.2474
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A237 - 656
2X-RAY DIFFRACTION2C26 - 169
3X-RAY DIFFRACTION3D26 - 174
4X-RAY DIFFRACTION4B239 - 443

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