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- PDB-2r4b: ErbB4 kinase domain complexed with a thienopyrimidine inhibitor -

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Basic information

Entry
Database: PDB / ID: 2r4b
TitleErbB4 kinase domain complexed with a thienopyrimidine inhibitor
ComponentsReceptor tyrosine-protein kinase erbB-4
KeywordsTRANSFERASE / Erb / kinase / ATP-binding / Glycoprotein / Membrane / Nucleotide-binding / Phosphorylation / Receptor / Transmembrane / Tyrosine-protein kinase
Function / homology
Function and homology information


establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / ERBB2-ERBB4 signaling pathway / mitochondrial fragmentation involved in apoptotic process / GABA receptor binding ...establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / ERBB2-ERBB4 signaling pathway / mitochondrial fragmentation involved in apoptotic process / GABA receptor binding / PI3K events in ERBB4 signaling / mammary gland epithelial cell differentiation / embryonic pattern specification / positive regulation of protein localization to cell surface / neurotransmitter receptor localization to postsynaptic specialization membrane / epidermal growth factor receptor activity / neural crest cell migration / epidermal growth factor receptor binding / ERBB2 Activates PTK6 Signaling / Signaling by ERBB4 / ERBB2 Regulates Cell Motility / cell surface receptor signaling pathway via JAK-STAT / Long-term potentiation / PI3K events in ERBB2 signaling / SHC1 events in ERBB4 signaling / GABA-ergic synapse / mammary gland alveolus development / cell fate commitment / Nuclear signaling by ERBB4 / regulation of cell migration / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of cardiac muscle cell proliferation / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / synapse assembly / Downregulation of ERBB4 signaling / lactation / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / basal plasma membrane / postsynaptic density membrane / Signaling by ERBB2 TMD/JMD mutants / positive regulation of receptor signaling pathway via JAK-STAT / neuromuscular junction / Signaling by ERBB2 KD Mutants / receptor protein-tyrosine kinase / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / presynaptic membrane / nervous system development / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / postsynaptic membrane / basolateral plasma membrane / protein tyrosine kinase activity / Estrogen-dependent gene expression / protein autophosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of ERK1 and ERK2 cascade / receptor complex / transcription cis-regulatory region binding / mitochondrial matrix / positive regulation of protein phosphorylation / negative regulation of cell population proliferation / glutamatergic synapse / positive regulation of cell population proliferation / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / signal transduction / protein homodimerization activity / mitochondrion / extracellular region / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / 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 / 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. / 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-GW7 / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsShewchuk, L.M. / Uehling, D.E.
CitationJournal: Proc.Natl.Acad.Sci.Usa / Year: 2008
Title: 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.
Authors: Wood, E.R. / Shewchuk, L.M. / Ellis, B. / Brignola, P. / Brashear, R.L. / Caferro, T.R. / Dickerson, S.H. / Dickson, H.D. / Donaldson, K.H. / Gaul, M. / Griffin, R.J. / Hassell, A.M. / ...Authors: Wood, E.R. / Shewchuk, L.M. / Ellis, B. / Brignola, P. / Brashear, R.L. / Caferro, T.R. / Dickerson, S.H. / Dickson, H.D. / Donaldson, K.H. / Gaul, M. / Griffin, R.J. / Hassell, A.M. / Keith, B. / Mullin, R. / Petrov, K.G. / Reno, M.J. / Rusnak, D.W. / Tadepalli, S.M. / Ulrich, J.C. / Wagner, C.D. / Vanderwall, D.E. / Waterson, A.G. / Williams, J.D. / White, W.L. / Uehling, D.E.
History
DepositionAug 31, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ncs_dom_lim / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _struct_ref_seq_dif.details / _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: Receptor tyrosine-protein kinase erbB-4
B: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,9354
Polymers73,1072
Non-polymers8282
Water2,468137
1
A: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9682
Polymers36,5541
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9682
Polymers36,5541
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)63.872, 63.872, 163.607
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number78
Space group name H-MP43
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GW7 / Beg label comp-ID: GW7 / End auth comp-ID: GW7 / End label comp-ID: GW7 / Refine code: 1 / Auth seq-ID: 1

Dom-IDAuth asym-IDLabel asym-ID
1AC
2BD

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Components

#1: Protein Receptor tyrosine-protein kinase erbB-4 / p180erbB4 / Tyrosine kinase-type cell surface receptor HER4


Mass: 36553.609 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB4, HER4 / Plasmid: pFastbac / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): SF-9
References: UniProt: Q15303, receptor protein-tyrosine kinase
#2: Chemical ChemComp-GW7 / N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-ethylthieno[3,2-d]pyrimidin-4-amine


Mass: 413.896 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H17ClFN3OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 137 / 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: 2.28 Å3/Da / Density % sol: 46.11 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 50mM Sodium cacodylate, 100mM amonium acetate, 10mM magnesium acetate, 30% PEG8000, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Apr 25, 2002 / Details: monochromoter
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→63.89 Å / Num. all: 22901 / Num. obs: 22901 / % possible obs: 94.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.3 % / Biso Wilson estimate: 59 Å2 / Rmerge(I) obs: 0.088 / Rsym value: 0.088 / Net I/σ(I): 27
Reflection shellResolution: 2.4→2.463 Å / Redundancy: 2 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 2 / Num. unique all: 864 / % possible all: 47

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1FGK

1fgk


Resolution: 2.4→63.89 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.93 / SU B: 20.97 / SU ML: 0.248 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R: 0.578 / ESU R Free: 0.3 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. TLS refinement was used.
RfactorNum. reflection% reflectionSelection details
Rfree0.26344 1234 5.1 %RANDOM
Rwork0.20578 ---
obs0.20857 22901 94.42 %-
all-24180 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 58.882 Å2
Baniso -1Baniso -2Baniso -3
1-1.56 Å20 Å20 Å2
2--1.56 Å20 Å2
3----3.13 Å2
Refinement stepCycle: LAST / Resolution: 2.4→63.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4574 0 56 137 4767
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0224764
X-RAY DIFFRACTIONr_angle_refined_deg1.1751.9886470
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3755585
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.41523.938193
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.29715827
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1751528
X-RAY DIFFRACTIONr_chiral_restr0.0760.2721
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023653
X-RAY DIFFRACTIONr_nbd_refined0.1940.22124
X-RAY DIFFRACTIONr_nbtor_refined0.3020.23188
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1240.2192
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2060.2119
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1340.223
X-RAY DIFFRACTIONr_mcbond_it0.3871.53005
X-RAY DIFFRACTIONr_mcangle_it0.6624731
X-RAY DIFFRACTIONr_scbond_it0.96132053
X-RAY DIFFRACTIONr_scangle_it1.5654.51737
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 28 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
tight positional0.030.05
tight thermal0.040.5
LS refinement shellResolution: 2.4→2.463 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.411 44 -
Rwork0.29 864 -
obs-864 47.19 %
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)
14.48950.2919-1.01811.139-0.46365.8617-0.3209-0.4163-0.03450.2191-0.0384-0.19240.32540.46960.35930.12990.14940.037-0.02370.0787-0.094-21.811414.91194.9077
24.0686-0.32161.30010.7891-0.1575.7935-0.33710.29430.036-0.2088-0.0508-0.1835-0.39320.38870.38790.1424-0.1622-0.046-0.10250.1001-0.03919.815916.9151-46.8838
32.76580.4473-0.57453.63650.51144.5925-0.2435-0.07470.12980.07220.1489-0.08670.08990.38390.0946-0.24670.0176-0.0402-0.1175-0.0006-0.2108-17.072727.9644-16.1535
42.7332-0.57830.73283.5470.71874.8608-0.23170.0732-0.1257-0.03850.1195-0.0932-0.08970.40270.1122-0.2481-0.01410.0457-0.12040.0107-0.210914.86054.0234-25.8041
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA694 - 80216 - 124
2X-RAY DIFFRACTION2BB694 - 80216 - 124
3X-RAY DIFFRACTION3AA803 - 991125 - 313
4X-RAY DIFFRACTION4BB803 - 991125 - 313

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