[English] 日本語
Yorodumi
- PDB-7v29: Crystal structure of FGFR4 with a dual-warhead covalent inhhibitor -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7v29
TitleCrystal structure of FGFR4 with a dual-warhead covalent inhhibitor
ComponentsFibroblast growth factor receptor 4
KeywordsTRANSFERASE / Inhibitor / Dual-warhead / Fibroblast growth factor receptor 4 / Covalent
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 / 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 / peptidyl-tyrosine phosphorylation / cholesterol homeostasis / Negative regulation of FGFR4 signaling / receptor protein-tyrosine kinase / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / glucose homeostasis / 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-5JR / Fibroblast growth factor receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.983 Å
AuthorsChen, X.J. / Jiang, L.Y. / Dai, S.Y. / Qu, L.Z. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81974074 China
National Natural Science Foundation of China (NSFC)81570537 China
CitationJournal: Commun Chem / Year: 2022
Title: Structure-based design of a dual-warhead covalent inhibitor of FGFR4.
Authors: Chen, X. / Li, H. / Lin, Q. / Dai, S. / Yue, S. / Qu, L. / Li, M. / Guo, M. / Wei, H. / Li, J. / Jiang, L. / Xu, G. / Chen, Y.
History
DepositionAug 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 30, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

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


Theoretical massNumber of molelcules
Total (without water)71,1329
Polymers69,3902
Non-polymers1,7427
Water7,584421
1
B: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6145
Polymers34,6951
Non-polymers9194
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint4 kcal/mol
Surface area14580 Å2
MethodPISA
2
A: Fibroblast growth factor receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5184
Polymers34,6951
Non-polymers8233
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1530 Å2
ΔGint-16 kcal/mol
Surface area14600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.421, 61.314, 76.531
Angle α, β, γ (deg.)90.000, 112.050, 90.000
Int Tables number4
Space group name H-MP1211

-
Components

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


Mass: 34695.059 Da / Num. of mol.: 2 / Mutation: R664E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR4, JTK2, TKF
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P22455, receptor protein-tyrosine kinase
#2: Chemical ChemComp-5JR / N-[2-[[3-(3,5-dimethoxyphenyl)-2-oxidanylidene-1-[3-(4-propanoylpiperazin-1-yl)propyl]-4H-pyrimido[4,5-d]pyrimidin-7-yl]amino]phenyl]propanamide


Mass: 630.737 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H42N8O5 / 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.: 421 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.18 Å3/Da / Density % sol: 43.46 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: 0.1 M Bis-Tris (pH 4.5), 0.2 M Li2SO4, 20% PEG 3350

-
Data collection

DiffractionMean temperature: 85 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97915 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 31, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 1.983→64.345 Å / Num. obs: 41464 / % possible obs: 99.81 % / Redundancy: 6.7 % / Biso Wilson estimate: 21.75 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.116 / Rrim(I) all: 0.1262 / Net I/σ(I): 10.96
Reflection shellResolution: 1.983→2.053 Å / Rmerge(I) obs: 0.3257 / Mean I/σ(I) obs: 2.37 / Num. unique obs: 4064 / CC1/2: 0.944

-
Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QRC

4qrc


Resolution: 1.983→64.345 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.241 2000 4.84 %
Rwork0.1914 39351 -
obs0.1938 41351 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.61 Å2 / Biso mean: 27.8686 Å2 / Biso min: 8.7 Å2
Refinement stepCycle: final / Resolution: 1.983→64.345 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4569 0 117 421 5107
Biso mean--36.03 34.54 -
Num. residues----583
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064807
X-RAY DIFFRACTIONf_angle_d0.9616526
X-RAY DIFFRACTIONf_chiral_restr0.044693
X-RAY DIFFRACTIONf_plane_restr0.005848
X-RAY DIFFRACTIONf_dihedral_angle_d14.0131851
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.983-2.03220.30561470.234270398
2.0322-2.08710.29491290.21862828100
2.0871-2.14860.26681400.20762771100
2.1486-2.21790.29321430.21242837100
2.2179-2.29720.25521580.2112788100
2.2972-2.38920.2461300.19732815100
2.3892-2.49790.24681490.18562813100
2.4979-2.62960.20251400.1882821100
2.6296-2.79430.25511450.19052792100
2.7943-3.01010.23961410.18572830100
3.0101-3.3130.2531500.18662820100
3.313-3.79240.23711410.17532837100
3.7924-4.77770.1971420.16532822100
4.7777-64.3450.23251450.2097287498

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more