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- PDB-5w21: Crystal Structure of a 1:1:1 FGF23-FGFR1c-aKlotho Ternary Complex -

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Basic information

Entry
Database: PDB / ID: 5w21
TitleCrystal Structure of a 1:1:1 FGF23-FGFR1c-aKlotho Ternary Complex
Components
  • (Fibroblast growth factor ...) x 2
  • Klotho
KeywordsHYDROLASE/PROTEIN BINDING / complex / ligand / receptor / co-receptor / HYDROLASE-PROTEIN BINDING complex
Function / homology
Function and homology information


type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions ...type 1 fibroblast growth factor receptor binding / FGFRL1 modulation of FGFR1 signaling / norepinephrine biosynthetic process / positive regulation of vitamin D 24-hydroxylase activity / beta-glucuronidase / Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / negative regulation of hormone secretion / beta-glucuronidase activity / FGFR1c and Klotho ligand binding and activation / vitamin D3 metabolic process / regulation of phosphate transport / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / cementum mineralization / intracellular phosphate ion homeostasis / vitamin D catabolic process / response to sodium phosphate / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / receptor-receptor interaction / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / auditory receptor cell development / ventricular zone neuroblast division / Epithelial-Mesenchymal Transition (EMT) during gastrulation / phosphate ion homeostasis / negative regulation of bone mineralization / positive regulation of parathyroid hormone secretion / chordate embryonic development / Signaling by activated point mutants of FGFR3 / FGFR3c ligand binding and activation / Phospholipase C-mediated cascade; FGFR3 / mesenchymal cell proliferation / fibroblast growth factor receptor binding / paraxial mesoderm development / cellular response to vitamin D / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / vitamin D binding / Phospholipase C-mediated cascade; FGFR2 / FGFR4 ligand binding and activation / energy reserve metabolic process / fibroblast growth factor receptor activity / FGFR1b ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / branching involved in salivary gland morphogenesis / Signaling by activated point mutants of FGFR1 / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / Phospholipase C-mediated cascade: FGFR1 / positive regulation of phospholipase activity / lung-associated mesenchyme development / response to vitamin D / cellular response to leptin stimulus / cellular response to interleukin-6 / cell projection assembly / negative regulation of systemic arterial blood pressure / cellular response to fibroblast growth factor stimulus / response to angiotensin / outer ear morphogenesis / middle ear morphogenesis / cellular response to parathyroid hormone stimulus / skeletal system morphogenesis / embryonic limb morphogenesis / ureteric bud development / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / cardiac muscle cell proliferation / positive regulation of endothelial cell chemotaxis / midbrain development / inner ear morphogenesis / PI-3K cascade:FGFR3 / fibroblast growth factor binding / beta-glucosidase activity / PI-3K cascade:FGFR2 / positive regulation of stem cell proliferation / PI-3K cascade:FGFR4 / Formation of paraxial mesoderm / PI-3K cascade:FGFR1 / regulation of cell differentiation / phosphatidylinositol-mediated signaling / response to magnesium ion / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / negative regulation of osteoblast differentiation / fibroblast growth factor receptor signaling pathway / calcium ion homeostasis / chondrocyte differentiation / positive regulation of bone mineralization / SHC-mediated cascade:FGFR3 / : / SHC-mediated cascade:FGFR2 / SHC-mediated cascade:FGFR4 / SHC-mediated cascade:FGFR1 / FRS-mediated FGFR3 signaling
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor family. / Fibroblast growth factor receptor family / Glycosyl hydrolases family 1, N-terminal conserved site / Glycosyl hydrolases family 1 N-terminal signature. / Cytokine IL1/FGF / Glycosyl hydrolase family 1 / Glycoside hydrolase family 1 ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor family / Fibroblast growth factor / Acidic and basic fibroblast growth factor family. / Fibroblast growth factor receptor family / Glycosyl hydrolases family 1, N-terminal conserved site / Glycosyl hydrolases family 1 N-terminal signature. / Cytokine IL1/FGF / Glycosyl hydrolase family 1 / Glycoside hydrolase family 1 / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Glycoside hydrolase superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulins / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Fibroblast growth factor receptor 1 / Fibroblast growth factor 23 / Klotho
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsMohammadi, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)DE13686 United States
CitationJournal: Nature / Year: 2018
Title: alpha-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling.
Authors: Chen, G. / Liu, Y. / Goetz, R. / Fu, L. / Jayaraman, S. / Hu, M.C. / Moe, O.W. / Liang, G. / Li, X. / Mohammadi, M.
History
DepositionJun 5, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2018Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.name
Revision 1.2Feb 7, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Feb 14, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.6Oct 4, 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
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Klotho
B: Fibroblast growth factor 23
C: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,06211
Polymers163,4493
Non-polymers1,6148
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10630 Å2
ΔGint-7 kcal/mol
Surface area57220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)283.301, 72.593, 95.329
Angle α, β, γ (deg.)90.00, 91.98, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Fibroblast growth factor ... , 2 types, 2 molecules BC

#2: Protein Fibroblast growth factor 23 / FGF-23 / Phosphatonin / Tumor-derived hypophosphatemia-inducing factor


Mass: 25406.482 Da / Num. of mol.: 1 / Fragment: UNP residues 25-204
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGF23, HYPF, UNQ3027/PRO9828 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9GZV9
#3: Protein Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 25375.973 Da / Num. of mol.: 1 / Fragment: D2 and D3 region (UNP residues 142-365)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase

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Protein / Sugars , 2 types, 8 molecules A

#1: Protein Klotho / alpha-Klotho


Mass: 112666.109 Da / Num. of mol.: 1 / Fragment: ectodomain (UNP residues 1-981)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KL / Production host: Homo sapiens (human) / References: UniProt: Q9UEF7, beta-glucuronidase
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 3.17 Å3/Da / Density % sol: 61.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 22% PEG350 MME, 0.1 M Tris-HCl, pH 8.0, 1 mM reduced glutathione, 1 mM oxidized glutathione

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 13, 2016
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. obs: 58000 / % possible obs: 99.7 % / Redundancy: 7.5 % / Net I/σ(I): 11.1
Reflection shellHighest resolution: 3 Å

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 2P39, 1CVS , & 2DGA

2p39

1cvs

2dga


Resolution: 3→48.801 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 37.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2782 1947 5 %
Rwork0.23 --
obs0.2324 38950 99.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→48.801 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10602 0 99 1 10702
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00211047
X-RAY DIFFRACTIONf_angle_d0.48315054
X-RAY DIFFRACTIONf_dihedral_angle_d11.3776433
X-RAY DIFFRACTIONf_chiral_restr0.041591
X-RAY DIFFRACTIONf_plane_restr0.0041939
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.0750.51891330.44412555X-RAY DIFFRACTION97
3.075-3.15820.44481390.39752612X-RAY DIFFRACTION99
3.1582-3.25110.40841380.34782622X-RAY DIFFRACTION100
3.2511-3.3560.36931370.33932602X-RAY DIFFRACTION99
3.356-3.47590.37061380.31212635X-RAY DIFFRACTION100
3.4759-3.6150.27041380.26142620X-RAY DIFFRACTION100
3.615-3.77950.28321380.24142644X-RAY DIFFRACTION100
3.7795-3.97870.29731380.21412642X-RAY DIFFRACTION100
3.9787-4.22780.23921390.19632630X-RAY DIFFRACTION100
4.2278-4.5540.26611410.18912674X-RAY DIFFRACTION100
4.554-5.01190.23821400.17432660X-RAY DIFFRACTION100
5.0119-5.73620.25791400.20042652X-RAY DIFFRACTION100
5.7362-7.22320.27791420.22252699X-RAY DIFFRACTION100
7.2232-48.80710.20051460.17682756X-RAY DIFFRACTION100
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)
11.77580.2573-0.9840.4602-0.10772.62580.0267-0.0651-0.13890.0098-0.0403-0.0075-0.06760.0952-0.01260.3680.069-0.07140.3858-0.01590.5033-28.005831.161744.626
21.14960.15390.41540.3480.08910.61030.039-0.28350.10420.07730.06750.21860.13-0.1431-0.11270.9530.06120.06681.02070.04670.7873-68.28521.734247.0297
30.9373-0.12990.2321.8404-0.39841.91170.18-0.1054-0.006-0.5001-0.04380.14740.5953-0.1453-0.14051.0727-0.0597-0.01570.8588-0.07860.8334-74.36566.065345.9385
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 34 through 1007)
2X-RAY DIFFRACTION2(chain 'B' and resid 19 through 200)
3X-RAY DIFFRACTION3(chain 'C' and resid 149 through 361)

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