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- PDB-6yi8: HUMAN FGFR4 KINASE DOMAIN (447-753) IN COMPLEX WITH ROBLITINIB -

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Basic information

Entry
Database: PDB / ID: 6yi8
TitleHUMAN FGFR4 KINASE DOMAIN (447-753) IN COMPLEX WITH ROBLITINIB
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / TYROSINE KINASE INHIBITOR / COVALENT REVERSIBLE INHIBITOR / FGFR4 / ROBLITINIB
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 / 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-FGF / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 Å
AuthorsOstermann, N.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.
Authors: Fairhurst, R.A. / Knoepfel, T. / Buschmann, N. / Leblanc, C. / Mah, R. / Todorov, M. / Nimsgern, P. / Ripoche, S. / Niklaus, M. / Warin, N. / Luu, V.H. / Madoerin, M. / Wirth, J. / Graus- ...Authors: Fairhurst, R.A. / Knoepfel, T. / Buschmann, N. / Leblanc, C. / Mah, R. / Todorov, M. / Nimsgern, P. / Ripoche, S. / Niklaus, M. / Warin, N. / Luu, V.H. / Madoerin, M. / Wirth, J. / Graus-Porta, D. / Weiss, A. / Kiffe, M. / Wartmann, M. / Kinyamu-Akunda, J. / Sterker, D. / Stamm, C. / Adler, F. / Buhles, A. / Schadt, H. / Couttet, P. / Blank, J. / Galuba, I. / Trappe, J. / Voshol, J. / Ostermann, N. / Zou, C. / Berghausen, J. / Del Rio Espinola, A. / Jahnke, W. / Furet, P.
History
DepositionApr 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 24, 2024Group: 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

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 4
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,1799
Polymers68,6852
Non-polymers1,4937
Water4,288238
1
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1375
Polymers34,3431
Non-polymers7954
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0414
Polymers34,3431
Non-polymers6993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)183.707, 67.198, 53.114
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 34342.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
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.: 2 / Source method: obtained synthetically / Formula: C25H30N8O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 238 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.39 Å3/Da / Density % sol: 48.46 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: mixing 0.5 ul of protein solution (13 mg/ml in 50 mM HEPES pH 8.0, 100 mM NaCl, 3% glycerol, 1 mM TCEP and 2 mM roblitinib incubated for 1h on ice) with 0.5 ul of reservoir solution (13.5 % ...Details: mixing 0.5 ul of protein solution (13 mg/ml in 50 mM HEPES pH 8.0, 100 mM NaCl, 3% glycerol, 1 mM TCEP and 2 mM roblitinib incubated for 1h on ice) with 0.5 ul of reservoir solution (13.5 % PEG 3350, 0.1 M (NH4)2SO4, 0.1 M NaAc pH 4.25)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00001049042 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001049042 Å / Relative weight: 1
ReflectionResolution: 2.13→45.98 Å / Num. obs: 37439 / % possible obs: 99.3 % / Redundancy: 4.17 % / Biso Wilson estimate: 41.05 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.048 / Rrim(I) all: 0.055 / Χ2: 0.985 / Net I/σ(I): 19.01 / Num. measured all: 155994 / Scaling rejects: 36
Reflection shellResolution: 2.13→2.23 Å / Redundancy: 4.07 % / Rmerge(I) obs: 0.445 / Mean I/σ(I) obs: 3.89 / Num. unique obs: 153 / CC1/2: 0.999 / Rrim(I) all: 0.026 / % possible all: 97.3

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TYG

4tyg


Resolution: 2.13→45.98 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.923 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.208 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.217 / SU Rfree Blow DPI: 0.176 / SU Rfree Cruickshank DPI: 0.174
RfactorNum. reflection% reflectionSelection details
Rfree0.231 1634 4.36 %RANDOM
Rwork0.196 ---
obs0.198 37437 99.3 %-
Displacement parametersBiso max: 137.48 Å2 / Biso mean: 45.28 Å2 / Biso min: 18.97 Å2
Baniso -1Baniso -2Baniso -3
1-7.5945 Å20 Å20 Å2
2---2.5328 Å20 Å2
3----5.0617 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 2.13→45.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4318 0 99 238 4655
Biso mean--54.7 50.87 -
Num. residues----547
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1560SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes101HARMONIC2
X-RAY DIFFRACTIONt_gen_planes648HARMONIC5
X-RAY DIFFRACTIONt_it4544HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion543SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5265SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4544HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6173HARMONIC21.03
X-RAY DIFFRACTIONt_omega_torsion3.06
X-RAY DIFFRACTIONt_other_torsion17.08
LS refinement shellResolution: 2.13→2.19 Å / Rfactor Rfree error: 0 / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.313 122 4.42 %
Rwork0.227 2639 -
all0.231 2761 -
obs--95.86 %

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