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- PDB-3lzb: EGFR kinase domain complexed with an imidazo[2,1-b]thiazole inhibitor -

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Basic information

Entry
Database: PDB / ID: 3lzb
TitleEGFR kinase domain complexed with an imidazo[2,1-b]thiazole inhibitor
ComponentsEpidermal growth factor receptor
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / epidermal growth factor kinase domain / multitargeted small molecule kinase inhibitor / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma ...positive regulation of protein kinase C activity / multivesicular body, internal vesicle lumen / positive regulation of prolactin secretion / negative regulation of cardiocyte differentiation / response to hydroxyisoflavone / diterpenoid metabolic process / Shc-EGFR complex / Inhibition of Signaling by Overexpressed EGFR / ovulation cycle / EGFR interacts with phospholipase C-gamma / positive regulation of mucus secretion / epidermal growth factor binding / regulation of peptidyl-tyrosine phosphorylation / tongue development / response to UV-A / PLCG1 events in ERBB2 signaling / midgut development / ERBB2-EGFR signaling pathway / hydrogen peroxide metabolic process / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / Signaling by EGFR / response to cobalamin / intracellular vesicle / negative regulation of epidermal growth factor receptor signaling pathway / eyelid development in camera-type eye / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of bone resorption / Signaling by ERBB4 / PI3K events in ERBB2 signaling / negative regulation of mitotic cell cycle / positive regulation of phosphorylation / MAP kinase kinase kinase activity / hair follicle development / peptidyl-tyrosine autophosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / positive regulation of peptidyl-serine phosphorylation / salivary gland morphogenesis / positive regulation of vasoconstriction / placental growth factor receptor activity / positive regulation of glial cell proliferation / hepatocyte growth factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / stem cell factor receptor activity / platelet-derived growth factor beta-receptor activity / brain-derived neurotrophic factor receptor activity / platelet-derived growth factor alpha-receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / insulin-like growth factor receptor activity / macrophage colony-stimulating factor receptor activity / Signaling by ERBB2 / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / EGFR Transactivation by Gastrin / GPI-linked ephrin receptor activity / vascular endothelial growth factor receptor activity / GRB2 events in ERBB2 signaling / fibroblast growth factor receptor activity / SHC1 events in ERBB2 signaling / insulin receptor activity / positive regulation of synaptic transmission, glutamatergic / cellular response to dexamethasone stimulus / ossification / liver regeneration / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of epithelial cell proliferation / positive regulation of superoxide anion generation / epithelial cell proliferation / positive regulation of DNA replication / neuron projection morphogenesis / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / astrocyte activation / cellular response to amino acid stimulus / NOTCH3 Activation and Transmission of Signal to the Nucleus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of smooth muscle cell proliferation / cellular response to estradiol stimulus / lung development / EGFR downregulation / synaptic membrane / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / peptidyl-tyrosine phosphorylation / Constitutive Signaling by EGFRvIII
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 / 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. / 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-ITI / Epidermal growth factor receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsSwinger, K.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Imidazo[2,1-b]thiazoles: multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family of receptor tyrosine kinases.
Authors: Fidanze, S.D. / Erickson, S.A. / Wang, G.T. / Mantei, R. / Clark, R.F. / Sorensen, B.K. / Bamaung, N.Y. / Kovar, P. / Johnson, E.F. / Swinger, K.K. / Stewart, K.D. / Zhang, Q. / Tucker, L.A. ...Authors: Fidanze, S.D. / Erickson, S.A. / Wang, G.T. / Mantei, R. / Clark, R.F. / Sorensen, B.K. / Bamaung, N.Y. / Kovar, P. / Johnson, E.F. / Swinger, K.K. / Stewart, K.D. / Zhang, Q. / Tucker, L.A. / Pappano, W.N. / Wilsbacher, J.L. / Wang, J. / Sheppard, G.S. / Bell, R.L. / Davidsen, S.K. / Hubbard, R.D.
History
DepositionMar 1, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 13, 2021Group: Database references / Derived calculations / Category: database_2 / 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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Epidermal growth factor receptor
B: Epidermal growth factor receptor
C: Epidermal growth factor receptor
D: Epidermal growth factor receptor
E: Epidermal growth factor receptor
F: Epidermal growth factor receptor
G: Epidermal growth factor receptor
H: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)291,45112
Polymers289,1008
Non-polymers2,3514
Water2,738152
1
A: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7252
Polymers36,1371
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7252
Polymers36,1371
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7252
Polymers36,1371
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Epidermal growth factor receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7252
Polymers36,1371
Non-polymers5881
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Epidermal growth factor receptor


  • defined by author&software
  • 36.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,1371
Polymers36,1371
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Epidermal growth factor receptor


  • defined by author&software
  • 36.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,1371
Polymers36,1371
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: Epidermal growth factor receptor


  • defined by author&software
  • 36.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,1371
Polymers36,1371
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: Epidermal growth factor receptor


  • defined by author&software
  • 36.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,1371
Polymers36,1371
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.586, 70.874, 115.182
Angle α, β, γ (deg.)90.00, 109.36, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Epidermal growth factor receptor / Receptor tyrosine-protein kinase erbB-1 / c-erbB-1


Mass: 36137.484 Da / Num. of mol.: 8 / Fragment: UNP residues 696-1022 / Mutation: V924R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB1 / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Hi5
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-ITI / N-[3-(5-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}imidazo[2,1-b][1,3]thiazol-6-yl)phenyl]-2-phenylacetamide


Mass: 587.694 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H29N7O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 152 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE ACTUAL CRYSTALLIZED SEQUENCE FOR THE LAST 39 C-TERMINAL RESIDUES IS ...THE ACTUAL CRYSTALLIZED SEQUENCE FOR THE LAST 39 C-TERMINAL RESIDUES IS DERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQG, CORRESPONDING TO THE UNP RESIDUES P00533:983-022. THESE RESIDUES WERE MODELED AS ALA IN CHAINS E,F,G,H AND WERE CHANGED TO UNK SINCE THE AUTHORS DO NOT KNOW THE CORRESPONDENCE BETWEEN THE SEQUENCE AND COORDINATES IN THIS REGION OF THE CHAINS.

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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

Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 7.7
Details: 0.15M cesium chloride, 15% w/v polyethylene glycol 3350, pH 7.7, VAPOR DIFFUSION, SITTING DROP, temperature 290K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 3, 2009 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 36061 / Num. obs: 36046 / % possible obs: 99.8 % / Redundancy: 3.7 % / Biso Wilson estimate: 62.974 Å2 / Rmerge(I) obs: 0.131 / Rsym value: 0.131 / Net I/σ(I): 13.55
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.52 / Mean I/σ(I) obs: 2.1 / Num. unique all: 3571 / Rsym value: 0.52 / % possible all: 76

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHASERphasing
BUSTER-TNT2.5.1refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2GS7

2gs7


Resolution: 2.7→44.17 Å / Cross valid method: THROUGHOUT / σ(F): 2.7 / σ(I): 2.7
RfactorNum. reflection% reflectionSelection details
Rfree0.2574 1801 5 %RANDOM
Rwork0.2037 ---
obs0.2064 36046 99.54 %-
all-36061 --
Displacement parametersBiso mean: 57.9 Å2
Baniso -1Baniso -2Baniso -3
1-11.6792929 Å20 Å220.33935063 Å2
2--1.40290831 Å20 Å2
3----13.08220121 Å2
Refinement stepCycle: LAST / Resolution: 2.7→44.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8561 0 172 152 8885
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.01189372
X-RAY DIFFRACTIONt_angle_deg1.326120542
X-RAY DIFFRACTIONt_dihedral_angle_d25.26817630
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.011742
X-RAY DIFFRACTIONt_gen_planes0.01513365
X-RAY DIFFRACTIONt_it2.087874120
X-RAY DIFFRACTIONt_nbd0.0671665
LS refinement shellResolution: 2.7→2.8 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2792 274 4.79 %
Rwork0.2208 5444 -
all0.2237 5718 -
obs-5718 99.54 %

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