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 | Osimertinib | Ligand Info | |||
| Canonical SMILES | CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC | ||||
| InChI | 1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32) | ||||
| InChIKey | DUYJMQONPNNFPI-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 71496458 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7JXW EGFR kinase (T790M/V948R) in complex with osimertinib and JBJ-09-063 | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [1] |
| PDB Sequence |
NQALLRILKE
709 TEFKKIKVLG719 SGAFGTVYKG729 LWIPEGEKVK739 IPVAIKELSP753 KANKEILDEA 763 YVMASVDNPH773 VCRLLGICLT783 STVQLIMQLM793 PFGCLLDYVR803 EHKDNIGSQY 813 LLNWCVQIAK823 GMNYLEDRRL833 VHRDLAARNV843 LVKTPQHVKI853 TDFGLVPIKW 880 MALESILHRI890 YTHQSDVWSY900 GVTVWELMTF910 GSKPYDGIPA920 SEISSILEKG 930 ERLPQPPICT940 IDVYMIMRKC950 WMIDADSRPK960 FRELIIEFSK970 MARDPQRYLV 980 IQGDERMHLP990 SPTDSNFYRA1000 LMDEEDM
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| PDB ID: 6JX0 Crystal structure of EGFR 696-1022 T790M in complex with AZD9291 prepared by co-crystallization | ||||||
| Method | X-ray diffraction | Resolution | 2.53 Å | Mutation | Yes | [2] |
| PDB Sequence |
QALLRILKET
710 EFKKIKVLGS720 GAFGTVYKGL730 WIPEGEKVKI740 PVAIKELREA750 TSPKANKEIL 760 DEAYVMASVD770 NPHVCRLLGI780 CLTSTVQLIM790 QLMPFGCLLD800 YVREHKDNIG 810 SQYLLNWCVQ820 IAKGMNYLED830 RRLVHRDLAA840 RNVLVKTPQH850 VKITDFGLAK 860 LLGAEEKEYH870 AEGGKVPIKW880 MALESILHRI890 YTHQSDVWSY900 GVTVWELMTF 910 GSKPYDGIPA920 SEISSILEKG930 ERLPQPPICT940 IDVYMIMVKC950 WMIDADSRPK 960 FRELIIEFSK970 MARDPQRYLV980 IQGDERMHL
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LEU718
3.438
GLY719
4.241
VAL726
2.993
LYS728
4.372
ALA743
3.524
LYS745
4.001
GLU749
4.915
ALA750
3.365
THR751
2.956
SER752
3.108
PRO753
3.412
ASN756
4.090
MET790
4.538
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| PDB ID: 6JX4 Crystal structure of EGFR 696-1022 T790M in complex with AZD9291 prepared by soaking | ||||||
| Method | X-ray diffraction | Resolution | 2.53 Å | Mutation | Yes | [2] |
| PDB Sequence |
GEAPNQALLR
705 ILKETEFKKI715 KVLGSGAFGT725 VYKGLWIPEG735 EKVKIPVAIK745 ELREATSPKA 755 NKEILDEAYV765 MASVDNPHVC775 RLLGICLTST785 VQLIMQLMPF795 GCLLDYVREH 805 KDNIGSQYLL815 NWCVQIAKGM825 NYLEDRRLVH835 RDLAARNVLV845 KTPQHVKITD 855 FGLAKLLGAE865 EKVPIKWMAL883 ESILHRIYTH893 QSDVWSYGVT903 VWELMTFGSK 913 PYDGIPASEI923 SSILEKGERL933 PQPPICTIDV943 YMIMVKCWMI953 DADSRPKFRE 963 LIIEFSKMAR973 DPQRYLVIQG983 DERMHLPSPT993 DSNFYRALMD1003 EEDMDDVVDA 1013 DEYLI
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| PDB ID: 6LUD Crystal Structure of EGFR(L858R/T790M/C797S) in complex with Osimertinib | ||||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | Yes | [3] |
| PDB Sequence |
GEAPNQALLR
705 ILKETEFKKI715 KVLGSGAFGT725 VYKGLWIPEG735 EKVKIPVAIK745 ELSPKANKEI 759 LDEAYVMASV769 DNPHVCRLLG779 ICLTSTVQLI789 MQLMPFGSLL799 DYVREHKDNI 809 GSQYLLNWCV819 QIAKGMNYLE829 DRRLVHRDLA839 ARNVLVKTPQ849 HVKITDFGRA 859 KLLGAAAAEY869 HAEGGKVPIK879 WMALESILHR889 IYTHQSDVWS899 YGVTVWELMT 909 FGSKPYDGIP919 ASEISSILEK929 GERLPQPPIC939 TIDVYMIMVK949 CWMIDADSRP 959 KFRELIIEFS969 KMARDPQRYL979 VIQGDERMHL989 PALMDEEDMD1008 DVVDADEYLI 1018
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Click to Show 3D Structure of This Binding Site
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. doi:10.1038/s41467-022-30258-y. | ||||
| REF 2 | Structural Basis of AZD9291 Selectivity for EGFR T790M. J Med Chem. 2020 Aug 13;63(15):8502-8511. | ||||
| REF 3 | CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation. Mol Cancer Ther. 2020 Nov;19(11):2288-2297. | ||||
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