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- PDB-5xff: Crystal structure of LY2874455 in complex of FGFR4 gatekeeper mut... -

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Basic information

Entry
Database: PDB / ID: 5xff
TitleCrystal structure of LY2874455 in complex of FGFR4 gatekeeper mutation (V550L)
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / inhibitor / kinase / gatekeeper / mutation
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-6LF / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.7 Å
AuthorsWu, D. / Chen, Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China81372904 China
National Natural Science Foundation of China81570537 China
National Natural Science Foundation of China81272971 China
CitationJournal: Chem. Commun. (Camb.) / Year: 2018
Title: LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance.
Authors: Wu, D. / Guo, M. / Min, X. / Dai, S. / Li, M. / Tan, S. / Li, G. / Chen, X. / Ma, Y. / Li, J. / Jiang, L. / Qu, L. / Zhou, Z. / Chen, Z. / Chen, L. / Xu, G. / Chen, Y.
History
DepositionApr 10, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 5, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _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: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1492
Polymers34,7051
Non-polymers4441
Water905
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13930 Å2
Unit cell
Length a, b, c (Å)62.291, 62.291, 184.586
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: 34705.102 Da / Num. of mol.: 1 / Mutation: V550L
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-6LF / 2-[4-[E-2-[5-[(1R)-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1H-indazol-3-yl]ethenyl]pyrazol-1-yl]ethanol / LY2874455


Mass: 444.314 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H19Cl2N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / 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: 2.58 Å3/Da / Density % sol: 52.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.65 M NH4H2PO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1.54178 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 28, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.7→39.75 Å / Num. obs: 10635 / % possible obs: 99.9 % / Redundancy: 26.6 % / Net I/σ(I): 29.63

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
HKL-3000data collection
HKL-3000data reduction
PHENIXphasing
RefinementResolution: 2.7→39.75 Å / SU ML: 0.41 / Cross valid method: NONE / σ(F): 1.34 / Phase error: 34.54
RfactorNum. reflection% reflection
Rfree0.3197 1053 9.98 %
Rwork0.2652 --
obs0.2704 10547 99.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.7→39.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2123 0 30 5 2158
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042210
X-RAY DIFFRACTIONf_angle_d0.8462998
X-RAY DIFFRACTIONf_dihedral_angle_d15.0151334
X-RAY DIFFRACTIONf_chiral_restr0.044326
X-RAY DIFFRACTIONf_plane_restr0.006385
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7005-2.82340.39471280.32141150X-RAY DIFFRACTION99
2.8234-2.97220.3371280.31531161X-RAY DIFFRACTION100
2.9722-3.15830.3421290.30171171X-RAY DIFFRACTION100
3.1583-3.4020.3691300.29841174X-RAY DIFFRACTION100
3.402-3.74420.34711250.31471130X-RAY DIFFRACTION96
3.7442-4.28540.28021300.25021169X-RAY DIFFRACTION98
4.2854-5.3970.30251360.23691223X-RAY DIFFRACTION100
5.397-39.75570.31831470.25111316X-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)
12.1964-0.69-2.85511.03922.17985.67571.03150.14410.25373.75280.00740.2922-0.0882-1.72420.52412.4231-0.3080.74311.01750.18260.570959.606135.3701575.7559
24.47571.3994-1.09655.01290.23183.91460.92970.10231.87730.2295-0.51471.3913-1.4397-1.0911-0.42511.32340.02120.09380.87530.03451.088466.224549.4526568.8871
34.08741.1545-2.81856.4751-1.15026.60721.2958-0.9884-0.35963.3767-1.6306-0.7932-2.4871.9339-0.10861.7699-0.38620.18150.7179-0.04231.034371.070344.481573.6513
41.87871.55211.91821.33881.45442.9842-0.6234-0.555-2.1076-0.7190.32750.17871.5925-0.4735-0.7551.3137-0.2047-0.06192.6263-0.35542.432650.665847.7642560.1221
55.0381-0.8583-0.87424.13811.36087.0754-0.2731.238-0.7873-0.16030.76312.29491.0288-0.4818-0.34080.8416-0.28510.16260.87650.05871.395659.384935.3525563.7618
65.75190.61890.19893.06851.83036.631-0.1984-0.996-0.86811.4939-0.22160.72350.05120.10440.0081.131-0.11750.10490.37370.07820.519166.516438.258568.9003
79.0541.1631-1.40124.252-1.69824.85960.78530.31711.95320.6161-0.2431-0.1725-0.5462-0.0853-0.16071.1081-0.26240.15330.75250.14081.122582.265248.0142552.4819
84.49581.1793-1.56052.96380.17014.868-0.50330.6931-0.00830.04510.3928-0.87610.11620.53330.21340.58270.0244-0.07940.61260.08490.756681.07632.8603552.1084
90.76911.7106-0.70253.5676-0.81890.6927-0.20990.75220.6638-1.78891.39164.0940.029-1.59580.44951.2511-0.16450.07761.5404-0.131.561565.951632.2453551.8189
103.8749-3.7257-3.72186.89930.83334.84350.1236-0.57140.71710.00760.07050.4833-0.1177-0.9782-0.18730.7802-0.24120.03420.82570.15960.822575.068239.4356557.0709
114.9972.70392.16633.94822.14934.055-0.9214-0.1211.1066-0.60880.12731.6740.18640.93970.36380.97920.45490.0221.5070.44740.905365.457739.705539.4409
127.3442-0.3898-0.50547.1394-1.05064.21210.91480.5307-0.8248-0.1041-0.17140.3506-0.0486-1.0811-0.65570.76370.0544-0.02540.99690.14050.681870.357334.7789541.835
135.98390.1177-6.71835.27431.47112.04280.83612.95263.00951.5165-0.22032.4763-3.4466-2.6769-1.21771.48430.28170.04360.92471.07751.45873.679347.1593535.8023
145.8395-1.72261.67774.65780.45623.95950.51861.1452-0.0899-0.2374-0.4702-0.5205-0.57790.30140.22370.91380.15130.01641.04140.14260.686977.048334.1917534.1367
157.319-1.2599-0.10521.4619-0.40452.66321.4750.1525-0.89670.3841-1.1764-0.37710.28340.4348-0.07880.8747-0.0381-0.12520.60570.17540.576584.693825.7707547.8537
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 453 through 463 )
2X-RAY DIFFRACTION2chain 'A' and (resid 464 through 480 )
3X-RAY DIFFRACTION3chain 'A' and (resid 481 through 507 )
4X-RAY DIFFRACTION4chain 'A' and (resid 508 through 513 )
5X-RAY DIFFRACTION5chain 'A' and (resid 514 through 527 )
6X-RAY DIFFRACTION6chain 'A' and (resid 528 through 550 )
7X-RAY DIFFRACTION7chain 'A' and (resid 551 through 570 )
8X-RAY DIFFRACTION8chain 'A' and (resid 583 through 605 )
9X-RAY DIFFRACTION9chain 'A' and (resid 606 through 614 )
10X-RAY DIFFRACTION10chain 'A' and (resid 615 through 633 )
11X-RAY DIFFRACTION11chain 'A' and (resid 651 through 661 )
12X-RAY DIFFRACTION12chain 'A' and (resid 662 through 683 )
13X-RAY DIFFRACTION13chain 'A' and (resid 684 through 697 )
14X-RAY DIFFRACTION14chain 'A' and (resid 698 through 735 )
15X-RAY DIFFRACTION15chain 'A' and (resid 736 through 750 )

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