Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T59328 | Target Info | |||
| Target Name | Epidermal growth factor receptor (EGFR) | ||||
| Synonyms | Receptor tyrosine-protein kinase erbB-1; Proto-oncogene c-ErbB-1; HER1; ERBB1; ERBB | ||||
| Target Type | Successful Target | ||||
| Gene Name | EGFR | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide | Ligand Info | |||
| Canonical SMILES | C1C2=CC=CC=C2C(=O)N1C(C3=C(C=CC(=C3)F)O)C(=O)NC4=NC=CS4 | ||||
| InChI | 1S/C19H14FN3O3S/c20-12-5-6-15(24)14(9-12)16(17(25)22-19-21-7-8-27-19)23-10-11-3-1-2-4-13(11)18(23)26/h1-9,16,24H,10H2,(H,21,22,25)/t16-/m1/s1 | ||||
| InChIKey | YTUFHOKUFOQRDF-MRXNPFEDSA-N | ||||
| PubChem Compound ID | 125461985 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5ZWJ Crystal structure of EGFR 675-1022 T790M/C797S/V948R in complex with EAI045 | ||||||
| Method | X-ray diffraction | Resolution | 2.90 Å | Mutation | Yes | [1] |
| PDB Sequence |
ALLRILKETE
711 FKKIKVLGSG721 AFGTVYKGLW731 IPEGEKVKIP741 VAIKELREAT751 SPKANKEILD 761 EAYVMASVDN771 PHVCRLLGIC781 LTSTVQLIMQ791 LMPFGSLLDY801 VREHKDNIGS 811 QYLLNWCVQI821 AKGMNYLEDR831 RLVHRDLAAR841 NVLVKTPQHV851 KITDFGLVPI 878 KWMALESILH888 RIYTHQSDVW898 SYGVTVWELM908 TFGSKPYDGI918 PASEISSILE 928 KGERLPQPPI938 CTIDVYMIMR948 KCWMIDADSR958 PKFRELIIEF968 SKMARDPQRY 978 LVIQGDE
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| PDB ID: 6Z4B Crystal Structure of EGFR-T790M/V948R in Complex with Osimertinib and EAI045 | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [2] |
| PDB Sequence |
NQALLRILKE
709 TEFKKIKVLG719 SGAFGTVYKG729 LWIPEGEKVK739 IPVAIKELRE749 ATSPKANKEI 759 LDEAYVMASV769 DNPHVCRLLG779 ICLTSTVQLI789 MQLMPFGCLL799 DYVREHKDNI 809 GSQYLLNWCV819 QIAKGMNYLE829 DRRLVHRDLA839 ARNVLVKTPQ849 HVKITDFGLA 859 KLLKVPIKWM881 ALESILHRIY891 THQSDVWSYG901 VTVWELMTFG911 SKPYDGIPAS 921 EISSILEKGE931 RLPQPPICTI941 DVYMIMRKCW951 MIDADSRPKF961 RELIIEFSKM 971 ARDPQRYLVI981 Q
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VAL726
3.732
ALA743
3.154
ILE744
3.863
LYS745
2.954
LEU747
4.150
ILE759
3.818
GLU762
4.868
ALA763
3.958
MET766
3.994
CYS775
3.308
ARG776
3.016
|
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| PDB ID: 7JXM EGFR kinase (T790M/V948R) in complex with osimertinib and EAI045 | ||||||
| Method | X-ray diffraction | Resolution | 2.19 Å | Mutation | Yes | [3] |
| PDB Sequence |
NQALLRILKE
709 TEFKKIKVLG719 SGAFGTVYKG729 LWIPEGEKVK739 IPVAIKELRE749 ATSPKANKEI 759 LDEAYVMASV769 DNPHVCRLLG779 ICLTSTVQLI789 MQLMPFGCLL799 DYVREHKDNI 809 GSQYLLNWCV819 QIAKGMNYLE829 DRRLVHRDLA839 ARNVLVKTPQ849 HVKITDFGLV 876 PIKWMALESI886 LHRIYTHQSD896 VWSYGVTVWE906 LMTFGSKPYD916 GIPASEISSI 926 LEKGERLPQP936 PICTIDVYMI946 MRKCWMIDAD956 SRPKFRELII966 EFSKMARDPQ 976 RYLVIQGDER986 MHLPSPTDSN996 FYRALMDEED1006 M
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VAL726
3.438
ALA743
3.263
ILE744
3.534
LYS745
3.237
LEU747
4.470
ILE759
3.395
GLU762
4.167
ALA763
3.819
MET766
3.928
CYS775
3.336
|
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| PDB ID: 6P1L Crystal structure of EGFR in complex with EAI045 | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [4] |
| PDB Sequence |
QALLRILKET
710 EFKKIKVLGS720 GAFGTVYKGL730 WIPEGEKVKI740 PVAIKELREA750 PKANKEILDE 762 AYVMASVDNP772 HVCRLLGICL782 TSTVQLIMQL792 MPFGCLLDYV802 REHKDNIGSQ 812 YLLNWCVQIA822 KGMNYLEDRR832 LVHRDLAARN842 VLVKTPQHVK852 ITDFGLVPIK 879 WMALESILHR889 IYTHQSDVWS899 YGVTVWELMT909 FGSKPYDGIP919 ASEISSILEK 929 GERLPQPPIC939 TIDVYMIMRK949 CWMIDADSRP959 KFRELIIEFS969 KMARDPQRYL 979 VIQGDERMHL989 PSPTDSNFYR999 ALMDEEDM
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .9LL or .9LL2 or .9LL3 or :39LL;style chemicals stick;color identity;select .A:723 or .A:726 or .A:743 or .A:744 or .A:745 or .A:747 or .A:759 or .A:762 or .A:763 or .A:766 or .A:775 or .A:776 or .A:777 or .A:788 or .A:789 or .A:790 or .A:854 or .A:855 or .A:856 or .A:857 or .A:858; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
PHE723
4.157
VAL726
3.595
ALA743
3.557
ILE744
3.756
LYS745
3.369
LEU747
4.502
ILE759
3.031
GLU762
4.014
ALA763
3.682
MET766
3.337
CYS775
3.316
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045. Biochem Biophys Res Commun. 2018 Jul 20;502(3):332-337. | ||||
| REF 2 | Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands. ACS Med Chem Lett. 2020 Nov 5;11(12):2484-2490. | ||||
| REF 3 | Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. doi:10.1038/s41467-022-30258-y. | ||||
| REF 4 | Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. ACS Med Chem Lett. 2019 Oct 22;10(11):1549-1553. | ||||
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