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

+
Open data


ID or keywords:

Loading...

-
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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / 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 / fibroblast growth factor receptor signaling pathway involved in mammary gland specification / lateral sprouting from an epithelium / mammary gland bud formation / branch elongation involved in salivary gland morphogenesis / mesenchymal cell differentiation involved in lung development / lacrimal gland development / otic vesicle formation / prostate gland morphogenesis / regulation of smooth muscle cell differentiation / orbitofrontal cortex development / regulation of morphogenesis of a branching structure / squamous basal epithelial stem cell differentiation involved in prostate gland acinus development / branching morphogenesis of a nerve / embryonic organ morphogenesis / endochondral bone growth / morphogenesis of embryonic epithelium / epidermis morphogenesis / bud elongation involved in lung branching / positive regulation of epithelial cell proliferation involved in lung morphogenesis / pyramidal neuron development / membranous septum morphogenesis / reproductive structure development / limb bud formation / lung lobe morphogenesis / gland morphogenesis / fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development / ventricular zone neuroblast division / embryonic digestive tract morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / mesenchymal cell differentiation / branching involved in prostate gland morphogenesis / mesenchymal cell proliferation involved in lung development / branching involved in labyrinthine layer morphogenesis / FGFR2b ligand binding and activation / FGFR2c ligand binding and activation / Activated point mutants of FGFR2 / regulation of osteoblast proliferation / Phospholipase C-mediated cascade; FGFR2 / fibroblast growth factor receptor activity / embryonic pattern specification / branching involved in salivary gland morphogenesis / outflow tract septum morphogenesis / positive regulation of phospholipase activity / lung-associated mesenchyme development / mesodermal cell differentiation / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / digestive tract development / bone morphogenesis / skeletal system morphogenesis / odontogenesis / ureteric bud development / ventricular cardiac muscle tissue morphogenesis / positive regulation of mesenchymal cell proliferation / regulation of osteoblast differentiation / Signaling by FGFR2 IIIa TM / midbrain development / organ growth / inner ear morphogenesis / hair follicle morphogenesis / lung alveolus development / fibroblast growth factor binding / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / PI-3K cascade:FGFR2 / bone mineralization / prostate epithelial cord elongation / positive regulation of cell division / excitatory synapse / PI3K Cascade / positive regulation of Wnt signaling pathway / negative regulation of keratinocyte proliferation / epithelial to mesenchymal transition / fibroblast growth factor receptor signaling pathway / cell fate commitment / embryonic organ development / positive regulation of cell cycle / SHC-mediated cascade:FGFR2 / cellular response to retinoic acid / positive regulation of cardiac muscle cell proliferation / FRS-mediated FGFR2 signaling / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / Signaling by FGFR2 in disease / epithelial cell differentiation / axonogenesis / regulation of ERK1 and ERK2 cascade / post-embryonic development / positive regulation of epithelial cell proliferation / Negative regulation of FGFR2 signaling / animal organ morphogenesis / lung development / bone development / receptor protein-tyrosine kinase / peptidyl-tyrosine phosphorylation / 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. / 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-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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

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

-
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

-
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

-
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

+
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://pdbjlvh1.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