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- PDB-5izq: Crystal structure of human folate receptor alpha in complex with ... -

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Basic information

Entry
Database: PDB / ID: 5izq
TitleCrystal structure of human folate receptor alpha in complex with novel antifolate AGF183
ComponentsFolate receptor alpha
KeywordsSIGNALING PROTEIN / Folate receptor alpha / antifolate / tumor targeting / 2-Amino-4-oxo-6-substituted pyrrolo[2 / 3-d]pyrimidine
Function / homology
Function and homology information


cellular response to folic acid / neural crest cell migration involved in heart formation / folic acid receptor activity / folic acid transport / sperm-egg recognition / fusion of sperm to egg plasma membrane involved in single fertilization / pharyngeal arch artery morphogenesis / cardiac neural crest cell migration involved in outflow tract morphogenesis / regulation of transforming growth factor beta receptor signaling pathway / anterior neural tube closure ...cellular response to folic acid / neural crest cell migration involved in heart formation / folic acid receptor activity / folic acid transport / sperm-egg recognition / fusion of sperm to egg plasma membrane involved in single fertilization / pharyngeal arch artery morphogenesis / cardiac neural crest cell migration involved in outflow tract morphogenesis / regulation of transforming growth factor beta receptor signaling pathway / anterior neural tube closure / Cargo concentration in the ER / regulation of canonical Wnt signaling pathway / COPII-mediated vesicle transport / clathrin-coated vesicle / axon regeneration / folic acid binding / heart looping / folic acid metabolic process / COPI-mediated anterograde transport / transport vesicle / endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis / brush border membrane / ER to Golgi transport vesicle membrane / signaling receptor activity / basolateral plasma membrane / cell adhesion / endosome / apical plasma membrane / Golgi membrane / external side of plasma membrane / endoplasmic reticulum membrane / cell surface / extracellular exosome / membrane / nucleus / plasma membrane
Similarity search - Function
Folate receptor / Folate receptor-like / Folate receptor family
Similarity search - Domain/homology
Chem-83A / Folate receptor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.6 Å
AuthorsKe, J. / Gu, X. / Brunzelle, J.S. / Xu, H.E. / Melcher, K.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK071662 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM102545 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM104212 United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate ...Title: Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
Authors: Golani, L.K. / Wallace-Povirk, A. / Deis, S.M. / Wong, J. / Ke, J. / Gu, X. / Raghavan, S. / Wilson, M.R. / Li, X. / Polin, L. / de Waal, P.W. / White, K. / Kushner, J. / O'Connor, C. / Hou, ...Authors: Golani, L.K. / Wallace-Povirk, A. / Deis, S.M. / Wong, J. / Ke, J. / Gu, X. / Raghavan, S. / Wilson, M.R. / Li, X. / Polin, L. / de Waal, P.W. / White, K. / Kushner, J. / O'Connor, C. / Hou, Z. / Xu, H.E. / Melcher, K. / Dann, C.E. / Matherly, L.H. / Gangjee, A.
History
DepositionMar 25, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Nov 1, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.4Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Sep 27, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.6Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Folate receptor alpha
B: Folate receptor alpha
C: Folate receptor alpha
D: Folate receptor alpha
E: Folate receptor alpha
F: Folate receptor alpha
G: Folate receptor alpha
H: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,82115
Polymers221,7248
Non-polymers3,0977
Water00
1
A: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Folate receptor alpha


Theoretical massNumber of molelcules
Total (without water)27,7161
Polymers27,7161
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: Folate receptor alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1582
Polymers27,7161
Non-polymers4421
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)90.793, 144.982, 211.252
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(0.385206, 0.919361, -0.07995), (-0.919756, 0.389545, 0.048), (0.075273, 0.055045, 0.995643)12.56031, 21.99698, -14.95875
3given(0.014523, 0.995783, 0.090578), (0.995095, -0.005529, -0.098767), (-0.09785, 0.091569, -0.99098)-40.15498, 20.19332, -63.57041
4given(0.914876, 0.402115, -0.036123), (-0.400085, 0.914973, 0.052494), (0.05416, -0.033574, 0.997968)1.88786, 18.21986, 61.85276
5given(-0.703683, -0.705292, 0.085982), (0.70883, -0.688531, 0.153247), (-0.048883, 0.168784, 0.98444)-21.8763, 53.24887, 21.33908
6given(0.927177, 0.37343, 0.029885), (0.372345, -0.909815, -0.183292), (-0.041257, 0.181071, -0.982604)20.95043, 62.64008, -80.59119
7given(0.710552, -0.70138, -0.056411), (0.703263, 0.70524, 0.089766), (-0.023177, -0.103455, 0.994364)0.47367, -3.54963, 78.05347
8given(0.38167, -0.91958, 0.093279), (0.920161, 0.38756, 0.055691), (-0.087363, 0.064576, 0.994081)51.30849, 64.39351, 6.63613
DetailsMonomer according to Size exclusion chromatography

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Components

#1: Protein
Folate receptor alpha / FR-alpha / Adult folate-binding protein / FBP / Folate receptor 1 / Folate receptor / adult / KB ...FR-alpha / Adult folate-binding protein / FBP / Folate receptor 1 / Folate receptor / adult / KB cells FBP / Ovarian tumor-associated antigen MOv18


Mass: 27715.523 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FOLR1, FOLR / Plasmid: pcDNA6 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P15328
#2: Chemical
ChemComp-83A / N-(4-{[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)ethyl]amino}benzene-1-carbonyl)-L-glutamic acid / antifolate AGF183


Mass: 442.425 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C20H22N6O6
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: 63.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 10% (w/v) polyethylene glycol 10K, 0.1 M BIS-TRIS pH 6.5, 0.2 M potassium sodium tartrate tetrahydrate

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: liquid nitrogen
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.078 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 24, 2015
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.078 Å / Relative weight: 1
ReflectionResolution: 3.6→50 Å / Num. obs: 32930 / % possible obs: 99.7 % / Redundancy: 5.6 % / CC1/2: 0.984 / Rmerge(I) obs: 0.25 / Net I/σ(I): 9.8
Reflection shellResolution: 3.6→3.81 Å / Redundancy: 5.7 % / Rmerge(I) obs: 1.1 / Mean I/σ(I) obs: 1.8 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LRH

4lrh


Resolution: 3.6→47.11 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.01 / Phase error: 26.93 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.257 3001 4.84 %RANDOM
Rwork0.2162 ---
obs0.2182 32929 99.32 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.6→47.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13527 0 224 0 13751
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00514295
X-RAY DIFFRACTIONf_angle_d0.9119342
X-RAY DIFFRACTIONf_dihedral_angle_d15.2555066
X-RAY DIFFRACTIONf_chiral_restr0.0371841
X-RAY DIFFRACTIONf_plane_restr0.0052513
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.6-3.6590.38251120.3522841X-RAY DIFFRACTION99
3.659-3.72210.34781510.32452800X-RAY DIFFRACTION99
3.7221-3.78980.31931530.31362809X-RAY DIFFRACTION99
3.7898-3.86260.35111300.28782774X-RAY DIFFRACTION99
3.8626-3.94140.29641710.27052837X-RAY DIFFRACTION100
3.9414-4.02710.29261490.27242770X-RAY DIFFRACTION99
4.0271-4.12070.31021420.24292835X-RAY DIFFRACTION99
4.1207-4.22370.29741640.24282773X-RAY DIFFRACTION100
4.2237-4.33780.23271400.21572858X-RAY DIFFRACTION100
4.3378-4.46540.25571390.20052796X-RAY DIFFRACTION100
4.4654-4.60940.25951190.19082856X-RAY DIFFRACTION100
4.6094-4.7740.20771680.18872813X-RAY DIFFRACTION100
4.774-4.96490.20671410.17722812X-RAY DIFFRACTION100
4.9649-5.19060.24291540.17542793X-RAY DIFFRACTION100
5.1906-5.46390.18651440.17142794X-RAY DIFFRACTION100
5.4639-5.80570.22661220.17582860X-RAY DIFFRACTION100
5.8057-6.2530.28681200.1712842X-RAY DIFFRACTION100
6.253-6.88050.20751740.18062808X-RAY DIFFRACTION100
6.8805-7.87210.2452990.18182829X-RAY DIFFRACTION99
7.8721-9.90290.22681620.18662811X-RAY DIFFRACTION99
9.9029-47.11420.23551470.2062679X-RAY DIFFRACTION95

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