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- PDB-9uhi: FGFR1 kinase domain with a covalent inhibitor 9o -

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Basic information

Entry
Database: PDB / ID: 9uhi
TitleFGFR1 kinase domain with a covalent inhibitor 9o
ComponentsFibroblast growth factor receptor 1
KeywordsTRANSFERASE / Fibroblast growth factor receptor 1 / TRANSFERASE INHIBITOR
Function / homology
Function and homology information


Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway ...Signaling by FGFR1 amplification mutants / negative regulation of fibroblast growth factor production / positive regulation of mitotic cell cycle DNA replication / regulation of extrinsic apoptotic signaling pathway in absence of ligand / Signaling by plasma membrane FGFR1 fusions / diphosphate metabolic process / regulation of phosphate transport / FGFR1c and Klotho ligand binding and activation / regulation of lateral mesodermal cell fate specification / positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway / vitamin D3 metabolic process / cementum mineralization / regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling / response to sodium phosphate / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / receptor-receptor interaction / Epithelial-Mesenchymal Transition (EMT) during gastrulation / positive regulation of phospholipase activity / chordate embryonic development / auditory receptor cell development / positive regulation of parathyroid hormone secretion / mesenchymal cell proliferation / paraxial mesoderm development / FGFR1b ligand binding and activation / regulation of postsynaptic density assembly / Signaling by activated point mutants of FGFR1 / fibroblast growth factor receptor activity / FGFR1c ligand binding and activation / organ induction / Downstream signaling of activated FGFR1 / branching involved in salivary gland morphogenesis / Phospholipase C-mediated cascade: FGFR1 / lung-associated mesenchyme development / cell projection assembly / outer ear morphogenesis / embryonic limb morphogenesis / positive regulation of endothelial cell chemotaxis / positive regulation of vascular endothelial cell proliferation / positive regulation of mesenchymal cell proliferation / ureteric bud development / middle ear morphogenesis / skeletal system morphogenesis / inner ear morphogenesis / phosphatidylinositol-mediated signaling / PI-3K cascade:FGFR1 / Formation of paraxial mesoderm / positive regulation of stem cell proliferation / midbrain development / fibroblast growth factor binding / positive regulation of MAP kinase activity / regulation of cell differentiation / PI3K Cascade / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / positive regulation of blood vessel endothelial cell migration / cardiac muscle cell proliferation / chondrocyte differentiation / calcium ion homeostasis / cell maturation / SHC-mediated cascade:FGFR1 / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR1 signaling / cellular response to fibroblast growth factor stimulus / Signaling by FGFR1 in disease / positive regulation of neuron differentiation / NCAM signaling for neurite out-growth / SH2 domain binding / peptidyl-tyrosine phosphorylation / Negative regulation of FGFR1 signaling / Signal transduction by L1 / stem cell proliferation / skeletal system development / positive regulation of cell differentiation / stem cell differentiation / sensory perception of sound / receptor protein-tyrosine kinase / positive regulation of neuron projection development / neuron migration / neuron projection development / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / MAPK cascade / heparin binding / protein autophosphorylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / cytoplasmic vesicle / protein tyrosine kinase activity / angiogenesis / gene expression / in utero embryonic development / protein phosphorylation / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynapse / positive regulation of MAPK cascade / positive regulation of cell population proliferation / glutamatergic synapse
Similarity search - Function
Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / Immunoglobulin domain / Immunoglobulin I-set / Immunoglobulin I-set domain / : / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain ...Fibroblast growth factor receptor 1, catalytic domain / Fibroblast growth factor receptor family / Immunoglobulin / 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 / 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
: / Fibroblast growth factor receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 Å
AuthorsChen, X.J. / Chen, Y.H.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82202920 China
National Natural Science Foundation of China (NSFC)82172654 China
CitationJournal: J.Med.Chem. / Year: 2025
Title: Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1 H -indole-3-yl)-5 H -pyrrolo[2,3- b ]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance.
Authors: Deng, W. / Chen, X. / Yan, L. / Xiang, S. / Song, X. / Zhang, L. / Li, X. / Zhu, W. / Pei, J. / Lin, X. / Patterson, A.V. / Smaill, J.B. / Li, B. / Tu, Z. / Zhou, Y. / Chen, Y. / Lu, X.
History
DepositionApr 14, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 24, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 1
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,0299
Polymers70,5292
Non-polymers1,5007
Water10,016556
1
A: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1586
Polymers35,2651
Non-polymers8945
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint-17 kcal/mol
Surface area15600 Å2
MethodPISA
2
B: Fibroblast growth factor receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8703
Polymers35,2651
Non-polymers6062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint0 kcal/mol
Surface area14640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)211.430, 49.280, 66.550
Angle α, β, γ (deg.)90.00, 107.42, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Fibroblast growth factor receptor 1 / FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 ...FGFR-1 / Basic fibroblast growth factor receptor 1 / BFGFR / bFGF-R-1 / Fms-like tyrosine kinase 2 / FLT-2 / N-sam / Proto-oncogene c-Fgr


Mass: 35264.520 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR1, BFGFR, CEK, FGFBR, FLG, FLT2, HBGFR / Production host: Escherichia coli (E. coli)
References: UniProt: P11362, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1EPF / ~{N}-[1-methyl-3-[3-[1-(2-morpholin-4-ylethyl)pyrazol-4-yl]quinoxalin-5-yl]indol-6-yl]propanamide


Mass: 509.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N7O2 / 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.: 556 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.35 Å3/Da / Density % sol: 47.55 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 16% (w/v) PEG 8000, 0.2 M LiSO4, and 0.1 M MES, pH 6.5

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.76→34.75 Å / Num. obs: 64663 / % possible obs: 99.12 % / Redundancy: 6.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.04136 / Net I/σ(I): 26.45
Reflection shellResolution: 1.76→1.823 Å / Rmerge(I) obs: 0.1181 / Mean I/σ(I) obs: 9.5 / Num. unique obs: 5964 / CC1/2: 0.985 / % possible all: 92.39

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→34.75 Å / SU ML: 0.14 / Cross valid method: NONE / σ(F): 1.4 / Phase error: 18.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.197 3248 5.02 %
Rwork0.1614 --
obs0.1632 64658 99.14 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.76→34.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4660 0 101 556 5317
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0124869
X-RAY DIFFRACTIONf_angle_d1.2416612
X-RAY DIFFRACTIONf_dihedral_angle_d8.155669
X-RAY DIFFRACTIONf_chiral_restr0.081714
X-RAY DIFFRACTIONf_plane_restr0.012844
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.76-1.790.21661000.18722347X-RAY DIFFRACTION88
1.79-1.810.20581430.17792513X-RAY DIFFRACTION94
1.81-1.840.22571520.17822666X-RAY DIFFRACTION100
1.84-1.880.21731530.16612656X-RAY DIFFRACTION100
1.88-1.910.2161360.1682704X-RAY DIFFRACTION100
1.91-1.950.21811330.17112649X-RAY DIFFRACTION100
1.95-1.990.19291490.16772694X-RAY DIFFRACTION100
1.99-2.030.2081550.16682671X-RAY DIFFRACTION100
2.03-2.080.20581590.16482650X-RAY DIFFRACTION100
2.08-2.130.19971180.15652709X-RAY DIFFRACTION100
2.13-2.190.20561330.1552659X-RAY DIFFRACTION100
2.19-2.250.1961530.15912690X-RAY DIFFRACTION100
2.25-2.320.21611280.1652689X-RAY DIFFRACTION100
2.32-2.410.21361520.16532668X-RAY DIFFRACTION100
2.41-2.50.2011460.17262704X-RAY DIFFRACTION100
2.5-2.620.21261520.17142673X-RAY DIFFRACTION100
2.62-2.750.22411400.17392711X-RAY DIFFRACTION100
2.75-2.930.18971290.17152696X-RAY DIFFRACTION100
2.93-3.150.19431470.16622702X-RAY DIFFRACTION100
3.15-3.470.20011340.15392726X-RAY DIFFRACTION100
3.47-3.970.16821430.14462709X-RAY DIFFRACTION100
3.97-50.17041490.13652712X-RAY DIFFRACTION99
5-34.750.19591440.17472812X-RAY DIFFRACTION99

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