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- PDB-6jpe: Crystal structure of FGFR4 kinase domain with irreversible inhibitor 1 -

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Basic information

Entry
Database: PDB / ID: 6jpe
TitleCrystal structure of FGFR4 kinase domain with irreversible inhibitor 1
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / FGFR4 / irreversible inhibitor / 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 / fibroblast growth factor binding ...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 / fibroblast growth factor binding / positive regulation of catalytic activity / 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 / 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
Similarity search - Domain/homology
Chem-BYU / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.601 Å
AuthorsChen, X. / Dai, S. / Zhou, Z. / Chen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81570537 China
CitationJournal: J.Med.Chem. / Year: 2020
Title: Development of a Potent and Specific FGFR4 Inhibitor for the Treatment of Hepatocellular Carcinoma.
Authors: Rezende Miranda, R. / Fu, Y. / Chen, X. / Perino, J. / Cao, P. / Carpten, J. / Chen, Y. / Zhang, C.
History
DepositionMar 26, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 4, 2020Group: 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 1.3Nov 22, 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

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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)35,4074
Polymers34,6631
Non-polymers7443
Water8,413467
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-17 kcal/mol
Surface area15570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.502, 61.126, 61.412
Angle α, β, γ (deg.)90.00, 99.10, 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-BYU / N-[2-[[6-[2-[[2,6-bis(chloranyl)-3,5-dimethoxy-phenyl]amino]pyridin-3-yl]pyrimidin-4-yl]amino]-3-methyl-phenyl]prop-2-enamide


Mass: 551.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24Cl2N6O3 / 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
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 2.27 Å3/Da / Density % sol: 45.87 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1 M MES pH 5.5, 18% PEG4K, 0.15 M (NH4)2SO4, and 4% (v/v) formamide

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Data collection

DiffractionMean temperature: 85 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 25, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.6→31.89 Å / Num. obs: 40751 / % possible obs: 99.45 % / Redundancy: 6.8 % / CC1/2: 0.991 / Rmerge(I) obs: 0.07494 / Rrim(I) all: 0.081 / Net I/σ(I): 16.46
Reflection shellResolution: 1.601→1.658 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.2545 / Mean I/σ(I) obs: 5.5 / Num. unique obs: 4092 / CC1/2: 0.976 / % possible all: 99.98

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-3000data collection
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QRC

4qrc


Resolution: 1.601→31.89 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.34
RfactorNum. reflection% reflection
Rfree0.1829 2007 4.93 %
Rwork0.1519 --
obs0.1535 40745 99.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.601→31.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2343 0 48 467 2858
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092452
X-RAY DIFFRACTIONf_angle_d1.1333329
X-RAY DIFFRACTIONf_dihedral_angle_d18.7371486
X-RAY DIFFRACTIONf_chiral_restr0.069354
X-RAY DIFFRACTIONf_plane_restr0.008432
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6011-1.64120.19491440.15812788X-RAY DIFFRACTION100
1.6412-1.68550.18861460.14862734X-RAY DIFFRACTION100
1.6855-1.73510.22891380.15032776X-RAY DIFFRACTION100
1.7351-1.79110.18891460.14942738X-RAY DIFFRACTION100
1.7911-1.85520.19071430.15592758X-RAY DIFFRACTION99
1.8552-1.92940.19941320.16592706X-RAY DIFFRACTION98
1.9294-2.01720.18581420.14762800X-RAY DIFFRACTION100
2.0172-2.12360.18821250.14632772X-RAY DIFFRACTION100
2.1236-2.25660.19311490.15572769X-RAY DIFFRACTION100
2.2566-2.43070.17781230.1572735X-RAY DIFFRACTION98
2.4307-2.67520.20591570.16032782X-RAY DIFFRACTION100
2.6752-3.06210.20991460.16672802X-RAY DIFFRACTION100
3.0621-3.85690.17581640.14452753X-RAY DIFFRACTION99
3.8569-31.90050.14711520.14122825X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: 43.8358 Å / Origin y: 5.5366 Å / Origin z: 74.0816 Å
111213212223313233
T0.1096 Å2-0.0144 Å20.0101 Å2-0.1109 Å20.0017 Å2--0.113 Å2
L0.5233 °2-0.1262 °20.3174 °2-0.507 °2-0.1271 °2--0.7583 °2
S0.004 Å °-0.0148 Å °-0.0263 Å °-0.0147 Å °-0.0112 Å °0.0065 Å °0.0271 Å °0.0154 Å °0.0076 Å °
Refinement TLS groupSelection details: all

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