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- PDB-5fxs: IGFR-1R complex with a pyrimidine inhibitor. -

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Basic information

Entry
Database: PDB / ID: 5fxs
TitleIGFR-1R complex with a pyrimidine inhibitor.
ComponentsINSULIN-LIKE GROWTH FACTOR 1 RECEPTOR
KeywordsTRANSFERASE
Function / homology
Function and homology information


cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / insulin-like growth factor binding / protein transporter activity / negative regulation of muscle cell apoptotic process ...cardiac atrium development / negative regulation of cholangiocyte apoptotic process / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / insulin-like growth factor binding / protein transporter activity / negative regulation of muscle cell apoptotic process / cellular response to progesterone stimulus / positive regulation of DNA metabolic process / cellular response to zinc ion starvation / cellular response to aldosterone / insulin receptor complex / cellular response to testosterone stimulus / negative regulation of hepatocyte apoptotic process / insulin-like growth factor I binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / response to alkaloid / cellular response to angiotensin / positive regulation of protein-containing complex disassembly / dendritic spine maintenance / cellular response to insulin-like growth factor stimulus / insulin binding / response to L-glutamate / negative regulation of MAPK cascade / establishment of cell polarity / positive regulation of axon regeneration / amyloid-beta clearance / positive regulation of osteoblast proliferation / positive regulation of cytokinesis / Respiratory syncytial virus (RSV) attachment and entry / regulation of JNK cascade / insulin receptor substrate binding / estrous cycle / G-protein alpha-subunit binding / response to vitamin E / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / peptidyl-tyrosine autophosphorylation / cellular response to transforming growth factor beta stimulus / T-tubule / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to dexamethasone stimulus / cerebellum development / axonogenesis / insulin-like growth factor receptor signaling pathway / caveola / cellular response to estradiol stimulus / hippocampus development / cellular response to glucose stimulus / positive regulation of smooth muscle cell proliferation / insulin receptor binding / response to nicotine / receptor protein-tyrosine kinase / cellular response to mechanical stimulus / cellular response to amyloid-beta / cellular senescence / insulin receptor signaling pathway / positive regulation of cold-induced thermogenesis / protein tyrosine kinase activity / response to ethanol / positive regulation of MAPK cascade / protein autophosphorylation / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of cell migration / immune response / axon / intracellular membrane-bounded organelle / neuronal cell body / positive regulation of cell population proliferation / protein-containing complex binding / negative regulation of apoptotic process / signal transduction / ATP binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats ...Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / : / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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
ACETATE ION / Chem-OZN / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDegorce, S. / Boyd, S. / Curwen, J. / Ducray, R. / Halsall, C. / Jones, C. / Lach, F. / Lenz, E. / Pass, M. / Pass, S. ...Degorce, S. / Boyd, S. / Curwen, J. / Ducray, R. / Halsall, C. / Jones, C. / Lach, F. / Lenz, E. / Pass, M. / Pass, S. / Trigwell, C. / Norman, R. / Phillips, C.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of a Potent, Selective, Orally Bioavailable, and Efficacious Novel 2-(Pyrazol-4-ylamino)-pyrimidine Inhibitor of the Insulin-like Growth Factor-1 Receptor (IGF-1R).
Authors: Degorce, S.L. / Boyd, S. / Curwen, J.O. / Ducray, R. / Halsall, C.T. / Jones, C.D. / Lach, F. / Lenz, E.M. / Pass, M. / Pass, S. / Trigwell, C.
History
DepositionMar 2, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 19, 2016Provider: repository / Type: Initial release
Revision 1.1May 16, 2018Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jul 11, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_CSD / _citation.journal_id_ISSN ..._citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8515
Polymers35,1651
Non-polymers6864
Water4,936274
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.820, 66.110, 122.110
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR / INSULIN-LIKE GROWTH FACTOR I RECEPTOR / IGF-I RECEPTOR / IGFR-1R


Mass: 35165.305 Da / Num. of mol.: 1 / Fragment: KINASE, UNP RESIDUES 980-1286
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P08069, receptor protein-tyrosine kinase
#2: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-OZN / 2-[4-[4-[[(6Z)-5-chloranyl-6-pyrazolo[1,5-a]pyridin-3-ylidene-1H-pyrimidin-2-yl]amino]-3,5-dimethyl-pyrazol-1-yl]piperidin-1-yl]-N,N-dimethyl-ethanamide


Mass: 509.026 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31ClN9O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 49.01 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Type: ESRF / Wavelength: 1
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 25378 / % possible obs: 99 % / Observed criterion σ(I): 1 / Redundancy: 5 % / Rmerge(I) obs: 0.06

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Processing

SoftwareName: REFMAC / Version: 5.5.0090 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 1.9→38.71 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.929 / SU B: 6.15 / SU ML: 0.08 / Cross valid method: THROUGHOUT / ESU R: 0.15 / ESU R Free: 0.13 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS THE SOLUBILIZING PART OF THE INHIBITOR, ATOMS C9, N10, C11, C13, C14, O15, N16, C17 AND C18 ARE NOT OBSERVED IN THE ELECTRON DENSITY. ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS THE SOLUBILIZING PART OF THE INHIBITOR, ATOMS C9, N10, C11, C13, C14, O15, N16, C17 AND C18 ARE NOT OBSERVED IN THE ELECTRON DENSITY. THEREFORE THEIR CONFORMATION IS OBSERVED EXPERIMENTALLY AND REFLECTS AT BEST A LOWEST ENERGY CONFORMATION.
RfactorNum. reflection% reflectionSelection details
Rfree0.21356 1342 5 %RANDOM
Rwork0.18086 ---
obs0.18253 25378 99.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.307 Å2
Baniso -1Baniso -2Baniso -3
1-0.48 Å20 Å20 Å2
2---0.05 Å20 Å2
3----0.43 Å2
Refinement stepCycle: LAST / Resolution: 1.9→38.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2358 0 48 274 2680
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022517
X-RAY DIFFRACTIONr_bond_other_d0.0010.021690
X-RAY DIFFRACTIONr_angle_refined_deg1.0971.963419
X-RAY DIFFRACTIONr_angle_other_deg0.96934110
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.495320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.27523.1100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.31815410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.0861518
X-RAY DIFFRACTIONr_chiral_restr0.0630.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022864
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02535
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4611.51574
X-RAY DIFFRACTIONr_mcbond_other0.0761.5631
X-RAY DIFFRACTIONr_mcangle_it0.8822527
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4483943
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.4834.5889
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.231 87 -
Rwork0.195 1874 -
obs--99.95 %
Refinement TLS params.Method: refined / Origin x: 17.1666 Å / Origin y: 4.2602 Å / Origin z: 46.3853 Å
111213212223313233
T0.0012 Å2-0.0021 Å20.0013 Å2-0.0064 Å2-0.0033 Å2--0.0037 Å2
L0.4988 °2-0.0729 °20.0759 °2-0.5029 °2-0.1283 °2--0.4255 °2
S-0.0159 Å °0.0557 Å °-0.0247 Å °0.0019 Å °-0.0071 Å °0.0101 Å °-0.0011 Å °0.0037 Å °0.023 Å °

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