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- PDB-3bbt: crystal structure of the ErbB4 kinase in complex with lapatinib -

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Basic information

Entry
Database: PDB / ID: 3bbt
Titlecrystal structure of the ErbB4 kinase in complex with lapatinib
ComponentsReceptor tyrosine-protein kinase erbB-4
KeywordsTRANSFERASE / inactive kinase conformation / ATP-binding / Glycoprotein / Membrane / Nucleotide-binding / Phosphoprotein / 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 / neural crest cell migration / epidermal growth factor receptor activity / 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 / SHC1 events in ERBB2 signaling / neurogenesis / 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 / cell surface receptor protein tyrosine kinase signaling pathway / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / 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-FMM / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.8 Å
AuthorsQiu, C.
CitationJournal: Structure / Year: 2008
Title: Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase.
Authors: Qiu, C. / Tarrant, M.K. / Choi, S.H. / Sathyamurthy, A. / Bose, R. / Banjade, S. / Pal, A. / Bornmann, W.G. / Lemmon, M.A. / Cole, P.A. / Leahy, D.J.
History
DepositionNov 11, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: 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 / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id / _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
B: Receptor tyrosine-protein kinase erbB-4
D: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,1454
Polymers74,9832
Non-polymers1,1622
Water1,51384
1
B: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0732
Polymers37,4911
Non-polymers5811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: Receptor tyrosine-protein kinase erbB-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0732
Polymers37,4911
Non-polymers5811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.682, 102.682, 185.124
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21D

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / End auth comp-ID: GLN / End label comp-ID: GLN / Refine code: 4

Dom-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1ALAALABA683 - 9637 - 287
2GLNGLNDB684 - 9638 - 287

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Components

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


Mass: 37491.457 Da / Num. of mol.: 2
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): Sf9
References: UniProt: Q15303, receptor protein-tyrosine kinase
#2: Chemical ChemComp-FMM / N-{3-CHLORO-4-[(3-FLUOROBENZYL)OXY]PHENYL}-6-[5-({[2-(METHYLSULFONYL)ETHYL]AMINO}METHYL)-2-FURYL]-4-QUINAZOLINAMINE / Lapatinib


Mass: 581.058 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H26ClFN4O4S / Comment: inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 84 / 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: 3.76 Å3/Da / Density % sol: 70.98 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 4.3 M NaCl, 0.1 M Hepes, pH 7.0, 2% trifluoroethanol, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4C / Wavelength: 0.97893 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Aug 25, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97893 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 27122 / % possible obs: 99.9 % / Redundancy: 4.8 % / Rmerge(I) obs: 0.062 / Χ2: 1.003 / Net I/σ(I): 14.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.8-2.94.50.51427100.947199.6
2.9-3.024.80.32627300.965199.9
3.02-3.154.90.24326670.999199.9
3.15-3.324.90.14827020.997199.9
3.32-3.534.90.10527151.049199.9
3.53-3.84.80.07226920.9931100
3.8-4.184.90.05427041.0521100
4.18-4.784.90.04227210.9861100
4.78-6.024.90.04127270.9751100
6.02-304.80.03427541.06199.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMAC5.2.0019refinement
PDB_EXTRACT3.004data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→29.64 Å / Cor.coef. Fo:Fc: 0.889 / Cor.coef. Fo:Fc free: 0.841 / SU B: 30.916 / SU ML: 0.307 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.534 / ESU R Free: 0.343 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.289 1381 5.1 %RANDOM
Rwork0.251 ---
obs0.253 27083 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.178 Å2
Baniso -1Baniso -2Baniso -3
1--1.28 Å2-0.64 Å20 Å2
2---1.28 Å20 Å2
3---1.91 Å2
Refinement stepCycle: LAST / Resolution: 2.8→29.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4292 0 55 84 4431
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0224456
X-RAY DIFFRACTIONr_angle_refined_deg1.3491.9876026
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1695527
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.73323.297182
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.25815815
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.391531
X-RAY DIFFRACTIONr_chiral_restr0.0810.2668
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023264
X-RAY DIFFRACTIONr_nbd_refined0.1720.21929
X-RAY DIFFRACTIONr_nbtor_refined0.2960.22969
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.2100
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.10.233
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1130.24
X-RAY DIFFRACTIONr_mcbond_it0.1851.52759
X-RAY DIFFRACTIONr_mcangle_it0.31924332
X-RAY DIFFRACTIONr_scbond_it0.3632009
X-RAY DIFFRACTIONr_scangle_it0.5824.51694
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: B / Ens-ID: 1 / Number: 2091 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
MEDIUM POSITIONAL0.390.5
MEDIUM THERMAL0.172
LS refinement shellResolution: 2.8→2.875 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.41 93 -
Rwork0.405 1912 -
all-2005 -
obs--99.26 %
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)
122.99172.84714.35759.2054-0.67748.9794-0.4373-0.8490.30810.4919-0.45520.6864-0.5012-0.82440.89260.2628-0.12470.04320.0336-0.29210.5886-35.853661.144716.6335
23.05462.60341.95677.80781.82933.1935-0.0251-0.43960.67660.3115-0.28440.709-0.1019-0.33320.30940.1531-0.1717-0.02240.3404-0.00910.42-36.122449.350811.6288
35.31841.6211.23964.4487-0.25883.02670.3959-0.25050.21670.4037-0.2122-0.14090.17830.1755-0.18370.2073-0.1416-0.04270.2565-0.00210.3604-31.249740.56489.6905
45.91421.73870.15413.9485-0.56164.34960.3239-0.597-0.28920.5869-0.123-0.51450.33220.0232-0.20090.3502-0.1628-0.09060.26480.11330.4908-31.160629.183417.9849
54.70965.8873-4.140814.75955.799919.9211-1.69461.04380.36050.17981.16210.3670.4022-0.55190.53250.5701-0.3517-0.23990.13790.27590.2548-47.542215.83791.1412
613.59265.91984.272112.32997.48969.1662-0.06410.67450.9559-0.7137-0.1651-0.5911-0.4466-0.54080.2292-0.04580.1124-0.08260.33090.2950.7251-47.104958.1338-11.7098
76.913-1.12670.86032.0557-0.10531.82470.18910.43151.1097-0.1302-0.06150.2628-0.3822-0.0826-0.12760.1884-0.06780.02390.3590.14340.4448-35.314252.9807-9.313
83.42780.1352-1.81712.2442-0.46882.82290.1140.87510.051-0.52240.04730.11880.2233-0.2877-0.16120.2107-0.0553-0.04180.49530.07230.3759-25.871144.6031-19.3864
96.56652.43291.12544.77623.47027.83990.11010.5396-0.8243-0.30030.0305-0.60190.72750.6594-0.14060.1865-0.00490.06280.30310.08550.5521-16.208937.3098-13.0777
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B683 - 742
2X-RAY DIFFRACTION2B743 - 790
3X-RAY DIFFRACTION3B791 - 838
4X-RAY DIFFRACTION4B839 - 963
5X-RAY DIFFRACTION5B965 - 973
6X-RAY DIFFRACTION6D684 - 743
7X-RAY DIFFRACTION7D744 - 791
8X-RAY DIFFRACTION8D792 - 918
9X-RAY DIFFRACTION9D919 - 963

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