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- PDB-6jpj: Crystal structure of FGF401 in complex of FGFR4 -

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Basic information

Entry
Database: PDB / ID: 6jpj
TitleCrystal structure of FGF401 in complex of FGFR4
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FGF401 / reversible covalent inhibitor / FGFR4 / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / fibroblast growth factor receptor activity / Phospholipase C-mediated cascade; FGFR4 / positive regulation of DNA biosynthetic process / positive regulation of catalytic activity / fibroblast growth factor binding / PI-3K cascade:FGFR4 / positive regulation of proteolysis / regulation of lipid metabolic process / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / glucose homeostasis / heparin binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / protein autophosphorylation / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / Golgi apparatus / endoplasmic reticulum / extracellular region / ATP binding / plasma membrane
Similarity search - Function
Fibroblast growth factor receptor family / 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 ...Fibroblast growth factor receptor family / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FGF / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.638 Å
AuthorsZhou, Z. / Chen, X. / Chen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81372904, 81570537, 81272971 China
CitationJournal: Chem.Commun.(Camb.) / Year: 2019
Title: Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4.
Authors: Zhou, Z. / Chen, X. / Fu, Y. / Zhang, Y. / Dai, S. / Li, J. / Chen, L. / Xu, G. / Chen, Z. / Chen, Y.
History
DepositionMar 27, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 22, 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 / refine_hist
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_high

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3624
Polymers34,6631
Non-polymers6993
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint-27 kcal/mol
Surface area15580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.275, 60.931, 61.154
Angle α, β, γ (deg.)90.00, 98.56, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Fibroblast growth factor receptor 4 / FGFR-4


Mass: 34662.992 Da / Num. of mol.: 1 / Mutation: C477A,R664E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Escherichia coli (E. coli)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-FGF / N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-methanoyl-6-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide / Roblitinib / FGF-401


Mass: 506.557 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H30N8O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.25 Å3/Da / Density % sol: 45.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M MES pH 5.5, 20% PEG 4000, 0.15M (NH4)2SO4, 4% (v/v) formamide

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: Cu FINE FOCUS / Wavelength: 1.5 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 2.638→41.8 Å / Num. obs: 8724 / % possible obs: 95.25 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 14.36
Reflection shellResolution: 2.638→2.7 Å / Rmerge(I) obs: 0.18

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-3000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JKG

5jkg


Resolution: 2.638→41.8 Å / Hydrogen treatment: constr / SU ML: 0.36 / Cross valid method: FREE R-VALUE / Phase error: 24.95
RfactorNum. reflection% reflection
Rfree0.2433 461 5.29 %
Rwork0.1953 --
obs0.1978 8713 95.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.638→41.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2352 0 47 45 2444
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032462
X-RAY DIFFRACTIONf_angle_d0.6753343
X-RAY DIFFRACTIONf_dihedral_angle_d13.165957
X-RAY DIFFRACTIONf_chiral_restr0.026354
X-RAY DIFFRACTIONf_plane_restr0.002434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6375-3.01910.37041250.2672454X-RAY DIFFRACTION85
3.0191-3.80330.30411870.20932858X-RAY DIFFRACTION100
3.8033-41.80940.16551490.16262940X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 86.1129 Å / Origin y: 7.463 Å / Origin z: 74.1564 Å
111213212223313233
T0.2801 Å2-0.0267 Å20.0023 Å2-0.2807 Å2-0.0072 Å2--0.2565 Å2
L0.6798 °2-0.1777 °20.5653 °2-0.7132 °2-0.3144 °2--1.4659 °2
S0.069 Å °0.0261 Å °-0.048 Å °0.0033 Å °-0.088 Å °0.0495 Å °0.1455 Å °0.0458 Å °0.0035 Å °
Refinement TLS groupSelection details: all

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