Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T16538 | Target Info | |||
| Target Name | EGFR T790M mutant (EGFR T790M) | ||||
| Synonyms | Receptor tyrosine-protein kinase erbB-1 T790M mutant; Proto-oncogene c-ErbB-1 T790M mutant; HER1 T790M mutant; Epidermal growth factor receptor T790M mutant; ERBB1 T790M mutant; ERBB T790M mutant | ||||
| 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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| 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. | ||||
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