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- PDB-6nvh: FGFR4 complex with N-(2-((5-((2,6-dichloro-3,5-dimethoxybenzyl)ox... -

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Basic information

Entry
Database: PDB / ID: 6nvh
TitleFGFR4 complex with N-(2-((5-((2,6-dichloro-3,5-dimethoxybenzyl)oxy)pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex / TRANSFERASE
Function / homology
Function and homology information


FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process ...FGFR4 mutant receptor activation / betaKlotho-mediated ligand binding / regulation of extracellular matrix disassembly / positive regulation of catalytic activity / phosphate ion homeostasis / regulation of bile acid biosynthetic process / FGFR4 ligand binding and activation / Phospholipase C-mediated cascade; FGFR4 / fibroblast growth factor receptor activity / positive regulation of DNA biosynthetic process / PI-3K cascade:FGFR4 / fibroblast growth factor binding / regulation of lipid metabolic process / positive regulation of proteolysis / PI3K Cascade / fibroblast growth factor receptor signaling pathway / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / transport vesicle / FRS-mediated FGFR4 signaling / peptidyl-tyrosine phosphorylation / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / glucose homeostasis / PIP3 activates AKT signaling / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of ERK1 and ERK2 cascade / receptor complex / endosome / positive regulation of cell population proliferation / positive regulation of gene expression / endoplasmic reticulum / Golgi apparatus / 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. ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-XL6 / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsLin, X. / Smaill, J.B. / Squire, C.J.
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4.
Authors: Lin, X. / Yosaatmadja, Y. / Kalyukina, M. / Middleditch, M.J. / Zhang, Z. / Lu, X. / Ding, K. / Patterson, A.V. / Smaill, J.B. / Squire, C.J.
History
DepositionFeb 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 11, 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 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)34,5514
Polymers33,8671
Non-polymers6833
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.127, 64.127, 181.924
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 33867.207 Da / Num. of mol.: 1
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-XL6 / N-[2-({5-[(2,6-dichloro-3,5-dimethoxyphenyl)methoxy]pyrimidin-2-yl}amino)-3-methylphenyl]propanamide


Mass: 491.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24Cl2N4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O
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: 2.76 Å3/Da / Density % sol: 55.45 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 100mM Bis-tris pH 4.5, 200mM lithium sulphate, 12% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.9→45.52 Å / Num. obs: 30981 / % possible obs: 100 % / Redundancy: 13.1 % / Biso Wilson estimate: 37.9 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.023 / Net I/σ(I): 16.8
Reflection shellResolution: 1.9→1.94 Å / Redundancy: 11.5 % / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1946 / CC1/2: 0.623 / Rpim(I) all: 0.58 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XCU

4xcu


Resolution: 1.9→45.52 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.948 / SU B: 3.276 / SU ML: 0.093 / Cross valid method: THROUGHOUT / ESU R: 0.135 / ESU R Free: 0.124 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23364 1497 4.8 %RANDOM
Rwork0.21225 ---
obs0.21326 29402 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 39.829 Å2
Baniso -1Baniso -2Baniso -3
1-0.71 Å20 Å2-0 Å2
2--0.71 Å2-0 Å2
3----1.43 Å2
Refinement stepCycle: 1 / Resolution: 1.9→45.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2058 0 43 106 2207
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0132176
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172042
X-RAY DIFFRACTIONr_angle_refined_deg1.291.6412968
X-RAY DIFFRACTIONr_angle_other_deg1.2371.5724705
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.995275
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.95320.40499
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.28115337
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8151517
X-RAY DIFFRACTIONr_chiral_restr0.0660.2272
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022430
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02460
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5314.2571092
X-RAY DIFFRACTIONr_mcbond_other2.534.2541091
X-RAY DIFFRACTIONr_mcangle_it3.8426.3561363
X-RAY DIFFRACTIONr_mcangle_other3.8416.3591364
X-RAY DIFFRACTIONr_scbond_it2.694.4061084
X-RAY DIFFRACTIONr_scbond_other2.6894.4071085
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.2976.5431603
X-RAY DIFFRACTIONr_long_range_B_refined6.40148.7712413
X-RAY DIFFRACTIONr_long_range_B_other6.448.7762414
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.321 103 -
Rwork0.31 2129 -
obs--99.87 %

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