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- PDB-4d2r: Human IGF in complex with a Dyrk1B inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d2r
TitleHuman IGF in complex with a Dyrk1B inhibitor
ComponentsINSULIN-LIKE GROWTH FACTOR 1 RECEPTOR
KeywordsTRANSFERASE / KINASE / INHIBITOR / ONCOLOGY
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
Chem-DYK / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsDebreczeni, J.E. / Kettle, J.G. / Ballard, P. / Bardelle, C. / Butterworth, S. / Colclough, N. / Critchlow, S.E. / Fairley, G. / Fillery, S. / Graham, M.A. ...Debreczeni, J.E. / Kettle, J.G. / Ballard, P. / Bardelle, C. / Butterworth, S. / Colclough, N. / Critchlow, S.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / Hudson, K. / Mahmood, A. / Vincent, J. / Ward, R.A. / Whittaker, D.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors to Explore a Mek Resistance Hypothesis.
Authors: Kettle, J.G. / Ballard, P. / Bardelle, C. / Cockerill, M. / Colclough, N. / Critchlow, S.E. / Debreczeni, J.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / ...Authors: Kettle, J.G. / Ballard, P. / Bardelle, C. / Cockerill, M. / Colclough, N. / Critchlow, S.E. / Debreczeni, J.E. / Fairley, G. / Fillery, S. / Graham, M.A. / Goodwin, L. / Guichard, S. / Hudson, K. / Ward, R.A. / Whittaker, D.
History
DepositionMay 12, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Oct 23, 2019Group: Data collection / Experimental preparation ...Data collection / Experimental preparation / Other / Structure summary
Category: audit_author / exptl_crystal_grow / pdbx_database_status
Item: _audit_author.name / _exptl_crystal_grow.method / _pdbx_database_status.status_code_sf
Revision 1.3May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,0483
Polymers34,5821
Non-polymers4662
Water3,981221
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.154, 66.486, 121.593
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 RECEPTOR / INSULIN-LIKE GROWTH FAC IGF-I RECEPTOR / CD221 / INSULIN-LIKE ...INSULIN-LIKE GROWTH FACTOR RECEPTOR / INSULIN-LIKE GROWTH FAC IGF-I RECEPTOR / CD221 / INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR BETA CHAIN


Mass: 34581.676 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 985-1286
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P08069, receptor protein-tyrosine kinase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-DYK / N-{2-methoxy-4-[(1-methylpiperidin-4-yl)oxy]phenyl}-4-(1H-pyrrolo[2,3-c]pyridin-3-yl)pyrimidin-2-amine


Mass: 430.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 221 / Source method: isolated from a natural source / Formula: H2O

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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: 2.41 Å3/Da / Density % sol: 48.86 % / Description: NONE
Crystal growMethod: vapor diffusion / Details: 20% PEF3350, 0.2M MGCL2, 0.1M PCTP PH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Apr 20, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→20.54 Å / Num. obs: 19300 / % possible obs: 95.8 % / Observed criterion σ(I): 2 / Redundancy: 3.68 % / Biso Wilson estimate: 26.1 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 8.31
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 3.13 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 2.23 / % possible all: 84.5

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→18.58 Å / Cor.coef. Fo:Fc: 0.9398 / Cor.coef. Fo:Fc free: 0.903 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.228 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.172
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.221 984 5.11 %RANDOM
Rwork0.179 ---
obs0.1811 19257 95.59 %-
Displacement parametersBiso mean: 28.35 Å2
Baniso -1Baniso -2Baniso -3
1-1.829 Å20 Å20 Å2
2---1.9539 Å20 Å2
3---0.1249 Å2
Refine analyzeLuzzati coordinate error obs: 0.238 Å
Refinement stepCycle: LAST / Resolution: 2.1→18.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2340 0 33 221 2594
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012436HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.033301HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d844SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes59HARMONIC2
X-RAY DIFFRACTIONt_gen_planes351HARMONIC5
X-RAY DIFFRACTIONt_it2436HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion15.96
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion304SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3078SEMIHARMONIC4
LS refinement shellResolution: 2.1→2.21 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2141 125 4.94 %
Rwork0.1812 2405 -
all0.1827 2530 -
obs--95.59 %
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)
12.3045-0.1003-0.37711.0987-0.35691.6214-0.0538-0.2134-0.27570.2296-0.0557-0.10530.4450.23220.10960.16450.04060.00650.00350.0789-0.009521.8758-4.856460.8002
21.981-0.12930.31720.884-0.10930.995-0.00850.2393-0.05830.0068-0.00980.0921-0.02120.00020.0183-0.04720.00270.0114-0.03-0.0077-0.069214.36019.077339.5309
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|985 - A|1082 }
2X-RAY DIFFRACTION2{ A|1083 - A|1286 }

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