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- PDB-8e1x: FGFR2 kinase domain in complex with a Pyrazolo[1,5-a]pyrimidine a... -

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Basic information

Entry
Database: PDB / ID: 8e1x
TitleFGFR2 kinase domain in complex with a Pyrazolo[1,5-a]pyrimidine analog (Compound 29)
ComponentsFibroblast growth factor receptor 2
KeywordsSTRUCTURAL PROTEIN / FGFR / inhibitor / kinase / gatekeeper / hyperphosphatemia
Function / homology
Function and homology information


Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development ...Signaling by FGFR2 amplification mutants / Signaling by FGFR2 fusions / fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell / fibroblast growth factor receptor signaling pathway involved in hemopoiesis / fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow / lateral sprouting from an epithelium / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / prostate gland morphogenesis / otic vesicle formation / regulation of smooth muscle cell differentiation / regulation of morphogenesis of a branching structure / orbitofrontal cortex development / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / embryonic organ morphogenesis / branching morphogenesis of a nerve / endochondral bone growth / morphogenesis of embryonic epithelium / bud elongation involved in lung branching / epidermis morphogenesis / positive regulation of epithelial cell proliferation involved in lung morphogenesis / reproductive structure development / limb bud formation / membranous septum morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / lung lobe morphogenesis / mesenchymal cell differentiation / positive regulation of phospholipase activity / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in prostate gland morphogenesis / FGFR2b ligand binding and activation / branching involved in labyrinthine layer morphogenesis / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / Phospholipase C-mediated cascade; FGFR2 / regulation of osteoblast proliferation / branching involved in salivary gland morphogenesis / embryonic pattern specification / pyramidal neuron development / lung-associated mesenchyme development / embryonic cranial skeleton morphogenesis / outflow tract septum morphogenesis / regulation of smoothened signaling pathway / mesodermal cell differentiation / bone morphogenesis / digestive tract development / odontogenesis / positive regulation of mesenchymal cell proliferation / ureteric bud development / skeletal system morphogenesis / inner ear morphogenesis / lung alveolus development / organ growth / hair follicle morphogenesis / Signaling by FGFR2 IIIa TM / ventricular cardiac muscle tissue morphogenesis / regulation of osteoblast differentiation / PI-3K cascade:FGFR2 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / prostate epithelial cord elongation / bone mineralization / midbrain development / fibroblast growth factor binding / positive regulation of cell division / PI3K Cascade / excitatory synapse / epithelial to mesenchymal transition / cell fate commitment / fibroblast growth factor receptor signaling pathway / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / embryonic organ development / fibroblast growth factor receptor activity / cellular response to transforming growth factor beta stimulus / regulation of ERK1 and ERK2 cascade / SHC-mediated cascade:FGFR2 / positive regulation of cardiac muscle cell proliferation / positive regulation of vascular associated smooth muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of cell cycle / cellular response to retinoic acid / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / positive regulation of epithelial cell proliferation / animal organ morphogenesis / post-embryonic development / Negative regulation of FGFR2 signaling / lung development / peptidyl-tyrosine phosphorylation / receptor protein-tyrosine kinase / bone development / Constitutive Signaling by Aberrant PI3K in Cancer
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 / 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-U9P / Fibroblast growth factor receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsLei, H.-T. / Epling, L.B. / Deller, M.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3.
Authors: Shvartsbart, A. / Roach, J.J. / Witten, M.R. / Koblish, H. / Harris, J.J. / Covington, M. / Hess, R. / Lin, L. / Frascella, M. / Truong, L. / Leffet, L. / Conlen, P. / Beshad, E. / Klabe, R. ...Authors: Shvartsbart, A. / Roach, J.J. / Witten, M.R. / Koblish, H. / Harris, J.J. / Covington, M. / Hess, R. / Lin, L. / Frascella, M. / Truong, L. / Leffet, L. / Conlen, P. / Beshad, E. / Klabe, R. / Katiyar, K. / Kaldon, L. / Young-Sciame, R. / He, X. / Petusky, S. / Chen, K.J. / Horsey, A. / Lei, H.T. / Epling, L.B. / Deller, M.C. / Vechorkin, O. / Yao, W.
History
DepositionAug 11, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fibroblast growth factor receptor 2
B: Fibroblast growth factor receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,5394
Polymers75,6462
Non-polymers8932
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2020 Å2
ΔGint-14 kcal/mol
Surface area27320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.515, 77.482, 126.272
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEULEULEU(chain 'A' and (resid 468 through 484 or (resid 485...AA468 - 51930 - 81
12ALAALAPROPRO(chain 'A' and (resid 468 through 484 or (resid 485...AA523 - 55985 - 121
13PTRPTRMETMET(chain 'A' and (resid 468 through 484 or (resid 485...AA561 - 584123 - 146
14PTRPTRASNASN(chain 'A' and (resid 468 through 484 or (resid 485...AA586 - 591148 - 153
15GLUGLUASPASP(chain 'A' and (resid 468 through 484 or (resid 485...AA596 - 650158 - 212
16TYRTYRLEULEU(chain 'A' and (resid 468 through 484 or (resid 485...AA657 - 761219 - 323
27LEULEULEULEU(chain 'B' and (resid 468 through 469 or (resid 470...BB468 - 51930 - 81
28ALAALAPROPRO(chain 'B' and (resid 468 through 469 or (resid 470...BB523 - 55985 - 121
29PTRPTRMETMET(chain 'B' and (resid 468 through 469 or (resid 470...BB561 - 584123 - 146
210PTRPTRASNASN(chain 'B' and (resid 468 through 469 or (resid 470...BB586 - 591148 - 153
211GLUGLUASPASP(chain 'B' and (resid 468 through 469 or (resid 470...BB596 - 650158 - 212
212TYRTYRLEULEU(chain 'B' and (resid 468 through 469 or (resid 470...BB657 - 761219 - 323

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Components

#1: Protein Fibroblast growth factor receptor 2 / FGFR-2 / K-sam / KGFR / Keratinocyte growth factor receptor


Mass: 37823.207 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGFR2, BEK, KGFR, KSAM / Production host: Escherichia coli (E. coli)
References: UniProt: P21802, receptor protein-tyrosine kinase
#2: Chemical ChemComp-U9P / (5M)-N-methyl-5-{(6M,8S)-5-{[(3S)-oxolan-3-yl]amino}-6-[1-(propan-2-yl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-3-yl}pyridine-3-carboxamide


Mass: 446.505 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.47 Å3/Da / Density % sol: 50.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.2
Details: 0.1 M Sodium citrate pH 5.2; 28% w/w PEG 4,000; 0.2 M Ammonium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 4, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.68→66.04 Å / Num. obs: 14681 / % possible obs: 87.1 % / Redundancy: 12.6 % / Biso Wilson estimate: 50.33 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.44 / Net I/σ(I): 6.4
Reflection shellResolution: 2.68→2.98 Å / Rmerge(I) obs: 2.34 / Num. unique obs: 734 / CC1/2: 0.5 / % possible all: 51.2

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Processing

Software
NameVersionClassification
PHENIX1.17rc2_3619refinement
autoPROCdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4QQT

4qqt


Resolution: 2.68→66.04 Å / SU ML: 0.2987 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.9517
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2724 718 4.89 %
Rwork0.224 13951 -
obs0.2264 14669 67.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.13 Å2
Refinement stepCycle: LAST / Resolution: 2.68→66.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4455 0 66 23 4544
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00584623
X-RAY DIFFRACTIONf_angle_d0.96946288
X-RAY DIFFRACTIONf_chiral_restr0.0494696
X-RAY DIFFRACTIONf_plane_restr0.0058801
X-RAY DIFFRACTIONf_dihedral_angle_d13.69272758
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.68-2.880.3563160.3282354X-RAY DIFFRACTION8.65
2.88-3.170.39821030.31141854X-RAY DIFFRACTION45.67
3.17-3.630.30122040.26134098X-RAY DIFFRACTION99.15
3.63-4.570.25291790.20213320X-RAY DIFFRACTION80.36
4.58-66.040.24372160.20084325X-RAY DIFFRACTION99.69
Refinement TLS params.Method: refined / Origin x: 36.8997174165 Å / Origin y: -2.23533175561 Å / Origin z: -13.9185553809 Å
111213212223313233
T0.259794691742 Å20.0121816184244 Å2-0.00924506918595 Å2-0.134897648601 Å2-0.0603271888917 Å2--0.22428526813 Å2
L1.85160181964 °2-0.193282814761 °20.10170222968 °2-0.403234324937 °2-0.319438356979 °2--0.76607519724 °2
S-0.0538452434076 Å °-0.131555139474 Å °0.317979610366 Å °0.0779740054775 Å °0.0230028317435 Å °-0.0713502979297 Å °-0.19302835961 Å °-0.023078691072 Å °0.019138654667 Å °
Refinement TLS groupSelection details: all

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