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- PDB-7vjl: The crystal structure of FGFR4 kinase domain in complex with N-(5... -

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Entry
Database: PDB / ID: 7vjl
TitleThe crystal structure of FGFR4 kinase domain in complex with N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(2,2,2-trifluoroacetyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / fgfr4 / Transferase Inhibitor
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-7IF / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.90017299719 Å
AuthorsZhang, Z.M. / Wang, Y.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design.
Authors: Zhang, Z. / Wang, Y. / Chen, X. / Song, X. / Tu, Z. / Chen, Y. / Zhang, Z. / Ding, K.
History
DepositionSep 28, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 2.0May 4, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / entity_src_gen / pdbx_contact_author / pdbx_refine_tls / pdbx_struct_sheet_hbond / pdbx_validate_close_contact / pdbx_validate_torsion / refine / refine_ls_restr / refine_ls_shell / struct_conf / struct_conn / struct_mon_prot_cis
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _entity_src_gen.gene_src_common_name / _pdbx_refine_tls.L[1][1] / _pdbx_refine_tls.L[1][2] / _pdbx_refine_tls.L[1][3] / _pdbx_refine_tls.L[2][2] / _pdbx_refine_tls.L[2][3] / _pdbx_refine_tls.L[3][3] / _pdbx_refine_tls.S[1][1] / _pdbx_refine_tls.S[1][2] / _pdbx_refine_tls.S[1][3] / _pdbx_refine_tls.S[2][1] / _pdbx_refine_tls.S[2][2] / _pdbx_refine_tls.S[2][3] / _pdbx_refine_tls.S[3][1] / _pdbx_refine_tls.S[3][2] / _pdbx_refine_tls.S[3][3] / _pdbx_refine_tls.T[1][1] / _pdbx_refine_tls.T[1][2] / _pdbx_refine_tls.T[1][3] / _pdbx_refine_tls.T[2][2] / _pdbx_refine_tls.T[2][3] / _pdbx_refine_tls.T[3][3] / _pdbx_refine_tls.origin_x / _pdbx_refine_tls.origin_y / _pdbx_refine_tls.origin_z / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _refine.B_iso_mean / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.overall_SU_ML / _refine.pdbx_overall_phase_error / _refine_ls_restr.dev_ideal / _refine_ls_shell.R_factor_R_free / _refine_ls_shell.R_factor_R_work / _struct_mon_prot_cis.pdbx_omega_angle
Description: Ligand geometry / Provider: author / Type: Coordinate replacement
Revision 2.1Sep 7, 2022Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 2.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5094
Polymers67,6042
Non-polymers9052
Water00
1
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2542
Polymers33,8021
Non-polymers4521
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2542
Polymers33,8021
Non-polymers4521
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.37, 66.785, 184.174
Angle α, β, γ (deg.)90.0, 90.0, 90.0
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 33802.004 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF / Production host: Escherichia alba (bacteria)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-7IF / N-[5-(aminomethyl)-4-(2-methoxyethylamino)pyridin-2-yl]-7-[2,2,2-tris(fluoranyl)ethanoyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide


Mass: 452.430 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23F3N6O3 / Feature type: SUBJECT OF INVESTIGATION
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: 2.43 Å3/Da / Density % sol: 49.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 0.5m NH4H2PO4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CAMD / Beamline: GCPCC / Wavelength: 0.97869 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jun 22, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97869 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 15232 / % possible obs: 99.5 % / Redundancy: 4.4 % / Biso Wilson estimate: 47.6659209837 Å2 / CC1/2: 0.915 / Net I/σ(I): 10.14
Reflection shellResolution: 2.9→3 Å / Num. unique obs: 1491 / CC1/2: 0.779

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Processing

Software
NameVersionClassification
PHENIX1.9_1692+SVNrefinement
HKL-2000data scaling
Cootmodel building
PHASERphasing
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6JPJ

6jpj


Resolution: 2.90017299719→37.9076086709 Å / SU ML: 0.371544085451 / Cross valid method: FREE R-VALUE / σ(F): 1.37094337122 / Phase error: 25.8333953848
RfactorNum. reflection% reflection
Rfree0.273007589253 1509 10.0046409865 %
Rwork0.204653382216 13574 -
obs0.211575321392 15083 98.8530606895 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.90497332 Å2
Refinement stepCycle: LAST / Resolution: 2.90017299719→37.9076086709 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4122 0 64 0 4186
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002996659532344290
X-RAY DIFFRACTIONf_angle_d0.7852041655685827
X-RAY DIFFRACTIONf_chiral_restr0.0721141260256637
X-RAY DIFFRACTIONf_plane_restr0.00333753016453746
X-RAY DIFFRACTIONf_dihedral_angle_d12.18695767631581
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9002-2.99370.3266912039231360.2740782530561218X-RAY DIFFRACTION99.3396918562
2.9937-3.10070.3338528122081330.2395953735751204X-RAY DIFFRACTION99.5532390171
3.1007-3.22480.3049770522951360.2313057001521219X-RAY DIFFRACTION99.9262536873
3.2248-3.37150.2519149156251360.222140033311225X-RAY DIFFRACTION99.780058651
3.3715-3.54910.3251942134721370.1969683717491237X-RAY DIFFRACTION99.3492407809
3.5491-3.77130.2698286950191360.1935031841591214X-RAY DIFFRACTION98.6842105263
3.7713-4.06210.2539590403031370.1852687475491239X-RAY DIFFRACTION99.7101449275
4.0621-4.47030.2217108622921370.1668794305821243X-RAY DIFFRACTION99.1379310345
4.4703-5.11590.2387473262451370.1797902756331224X-RAY DIFFRACTION98.9098837209
5.1159-6.44030.2830540017261390.2122898127161249X-RAY DIFFRACTION97.9534227241
6.4403-100.2880512716671450.2259327670821302X-RAY DIFFRACTION95.5746367239
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)
18.559013452081.34019344683-0.0369480395965.969807195930.3617028409283.773526218-0.04252992385660.6592847261520.291997775976-0.6648680011510.1458455208390.467656222848-0.527118028619-0.184631133987-0.106795916260.640260246492-0.0670042115733-0.03796735718020.4864689762650.1082550495750.3349780842781.57583179371-3.41251387738-39.0117968318
23.754737801880.430039057127-0.5114063149593.19658762822-1.685883647846.00808831838-0.006554637045030.212359515172-0.0522758076157-0.7636715067040.1538964621230.634144367587-0.105328423014-0.308286029483-0.1387819048250.370110883783-0.0364615628371-0.03418434085910.274924014625-0.04082087149290.3009218315647.34386461117-12.3070500865-25.3469676951
31.482413053820.5712491902270.6610388866075.24567626761.720224470654.775339047840.155565780828-0.1656775420270.1059806564010.232880046702-0.0598777506201-0.03239796373460.007905225054430.00485065090442-0.102613998110.199921076134-0.008573602175090.03158158886260.23485512565-0.004503768854080.23492007840912.3731517179-10.4153897615-8.3782249295
44.530450354370.736131042072-0.8852973895785.19070815130.5044278186145.80847062313-0.1308222255520.12390974522-0.1303614788490.04482301549520.166321372307-0.3782457436480.4471022709990.269950290566-0.002148684974350.2553218496330.00602165779638-0.007752263773880.19121156736-0.02325955074420.2521922650136.111507483418.6596609795-2.20039039466
55.06794732689-4.65484093066-5.947448156654.350593880485.129190825448.30678163943-0.571716377623-0.575127080424-1.256579579510.1700777569660.1076448823410.07643414049141.112082264430.4614741074390.4616745740370.3005365754950.05062282901870.1307783707260.249232196595-0.01365021387240.45094307031440.384357881713.0483179897-8.94737170855
63.07842099043-0.9608960497322.021610334521.90293149896-0.9011987410422.54358983930.0324750031078-0.121641307076-0.15350169393-0.1928077701390.0432946653310.05429051037250.158591658135-0.0879006635711-0.02488292729670.238489058988-0.01107880791070.02162374990750.166800457702-0.07713797058480.15343237802831.897744749623.5092902961-17.2802842241
71.920994737790.4693684753722.475494706626.124710594662.713631690463.90913186956-0.3216865622040.138934920628-0.439844350774-0.6973306874120.426033643819-0.729361894030.01014112011130.391659672335-0.2260284038570.4272981305770.0367151375087-0.01761576634930.213577311494-0.0177167924820.31082360401731.909800173125.1369499369-21.8425126936
85.193613298271.92975921882-0.8556718808652.861767509730.755201965173.7970814125-0.3868181229060.876395402248-0.0147109855734-0.7196809771210.538223433214-0.2465383894880.176209314950.142697821434-0.2047663692820.8665982474820.1081018967560.01065549658330.484403056583-0.04496900025460.31732205708429.887917394527.9341129487-39.5619697404
94.121629711483.785418360091.880926698815.345281701611.635770528545.48033629810.409983243657-0.1808048733610.7782475392060.504210841852-0.6003333852740.657245745340.162067675097-0.3369168153250.09374164184640.755155109470.194502414710.005767182338260.328748190108-0.04932931750050.22995327879418.029296573337.8897013701-27.0076292635
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 454 through 527 )
2X-RAY DIFFRACTION2chain 'A' and (resid 528 through 625 )
3X-RAY DIFFRACTION3chain 'A' and (resid 626 through 753 )
4X-RAY DIFFRACTION4chain 'B' and (resid 453 through 496 )
5X-RAY DIFFRACTION5chain 'B' and (resid 497 through 510 )
6X-RAY DIFFRACTION6chain 'B' and (resid 511 through 605 )
7X-RAY DIFFRACTION7chain 'B' and (resid 606 through 652 )
8X-RAY DIFFRACTION8chain 'B' and (resid 653 through 735 )
9X-RAY DIFFRACTION9chain 'B' and (resid 736 through 753 )

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