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

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Basic information

Entry
Database: PDB / ID: 5fxr
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 / positive regulation of steroid hormone biosynthetic process / protein kinase complex / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / negative regulation of muscle cell apoptotic process / cellular response to progesterone stimulus ...cardiac atrium development / negative regulation of cholangiocyte apoptotic process / positive regulation of steroid hormone biosynthetic process / protein kinase complex / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / protein transporter activity / IRS-related events triggered by IGF1R / 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 / cellular response to testosterone stimulus / insulin receptor complex / transcytosis / insulin-like growth factor I binding / negative regulation of hepatocyte apoptotic process / positive regulation of protein-containing complex disassembly / alphav-beta3 integrin-IGF-1-IGF1R complex / response to alkaloid / regulation of JNK cascade / dendritic spine maintenance / insulin binding / cellular response to insulin-like growth factor stimulus / response to L-glutamate / establishment of cell polarity / positive regulation of axon regeneration / positive regulation of osteoblast proliferation / positive regulation of cytokinesis / amyloid-beta clearance / Respiratory syncytial virus (RSV) attachment and entry / insulin receptor substrate binding / cellular response to angiotensin / response to vitamin E / G-protein alpha-subunit binding / negative regulation of MAPK cascade / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / peptidyl-tyrosine autophosphorylation / estrous cycle / cellular response to transforming growth factor beta stimulus / T-tubule / cerebellum development / cellular response to dexamethasone stimulus / axonogenesis / insulin-like growth factor receptor signaling pathway / hippocampus development / phosphatidylinositol 3-kinase/protein kinase B signal transduction / response to nicotine / positive regulation of smooth muscle cell proliferation / insulin receptor binding / cellular response to estradiol stimulus / placental growth factor receptor activity / cellular response to glucose stimulus / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / caveola / cellular response to mechanical stimulus / cellular response to amyloid-beta / cellular senescence / insulin receptor signaling pathway / positive regulation of cold-induced thermogenesis / protein autophosphorylation / protein tyrosine kinase activity / response to ethanol / Extra-nuclear estrogen signaling / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / immune response / cilium / positive regulation of cell migration / axon / neuronal cell body / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / 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 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 / 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 / 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-8LN / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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)35,5872
Polymers35,1781
Non-polymers4091
Water3,495194
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.252, 67.331, 122.166
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: 35178.305 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-8LN / 5-chloranyl-4-imidazo[1,2-a]pyridin-3-yl-N-(3-methyl-1-piperidin-4-yl-pyrazol-4-yl)pyrimidin-2-amine


Mass: 408.887 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21ClN8
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 194 / 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: 48.99 % / 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: 2.4→29 Å / Num. obs: 13146 / % possible obs: 99 % / Observed criterion σ(I): 1 / Redundancy: 5 % / Rmerge(I) obs: 0.08

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Processing

SoftwareName: REFMAC / Version: 5.4.0069 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.4→28.98 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.874 / SU B: 9.716 / SU ML: 0.226 / Cross valid method: THROUGHOUT / ESU R: 0.54 / ESU R Free: 0.32 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29442 693 5 %RANDOM
Rwork0.22709 ---
obs0.23038 13146 99.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 43.009 Å2
Baniso -1Baniso -2Baniso -3
1-0.12 Å20 Å20 Å2
2--0.15 Å20 Å2
3----0.27 Å2
Refinement stepCycle: LAST / Resolution: 2.4→28.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2353 0 29 194 2576
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222464
X-RAY DIFFRACTIONr_bond_other_d0.0010.021651
X-RAY DIFFRACTIONr_angle_refined_deg1.4751.983339
X-RAY DIFFRACTIONr_angle_other_deg1.67534014
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0365302
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.49624.054111
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.54615413
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2861515
X-RAY DIFFRACTIONr_chiral_restr0.0720.2357
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212775
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02503
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_it0.4411.51502
X-RAY DIFFRACTIONr_mcbond_other0.0741.5608
X-RAY DIFFRACTIONr_mcangle_it0.82622418
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.2733962
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.0094.5919
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: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 61 -
Rwork0.238 934 -
obs--99.5 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.59890.0748-1.75450.14630.10861.4534-0.3695-0.3011-0.1060.11180.1022-0.04730.26830.49540.26720.1570.0126-0.04750.00720.0562-0.001433.228-7.027862.313
21.7347-0.2301-2.76333.5903-3.91849.55970.16171.3692-0.3430.4555-0.46330.60450.35350.49840.30160.00030.0221-0.051-0.0175-0.04880.080912.0004-4.447752.7598
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A979 - 1283
2X-RAY DIFFRACTION2A2284

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