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 | 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: 6JXT Crystal structure of EGFR 696-1022 WT in complex with AZD9291 prepared by cocrystallization | ||||||
| Method | X-ray diffraction | Resolution | 2.31 Å | Mutation | Yes | [1] |
| PDB Sequence |
EAPNQALLRI
706 LKETEFKKIK716 VLGSGAFGTV726 YKGLWIPEGE736 KVKIPVAIKE746 LRESPKANKE 758 ILDEAYVMAS768 VDNPHVCRLL778 GICLTSTVQL788 ITQLMPFGCL798 LDYVREHKDN 808 IGSQYLLNWC818 VQIAKGMNYL828 EDRRLVHRDL838 AARNVLVKTP848 QHVKITDFGL 858 AKLLGAAAEY869 HAEGKVPIKW880 MALESILHRI890 YTHQSDVWSY900 GVTVWELMTF 910 GSKPYDGIPA920 SEISSILEKG930 ERLPQPPICT940 IDVYMIMVKC950 WMIDADSRPK 960 FRELIIEFSK970 MARDPQRYLV980 IQGD
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LEU718
3.562
GLY719
3.631
SER720
4.911
PHE723
4.787
VAL726
3.668
LYS728
4.699
ALA743
3.596
LYS745
3.125
THR790
4.355
GLN791
3.690
LEU792
3.730
MET793
3.185
|
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| 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 | [2] |
| 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 | [1] |
| 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 | [1] |
| 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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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .YY3 or .YY32 or .YY33 or :3YY3;style chemicals stick;color identity;select .A:718 or .A:719 or .A:726 or .A:728 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:794 or .A:795 or .A:796 or .A:797 or .A:800 or .A:841 or .A:844 or .A:1001; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 6JWL Crystal structure of EGFR 696-1022 L858R in complex with AZD9291 | ||||||
| Method | X-ray diffraction | Resolution | 2.55 Å | Mutation | Yes | [1] |
| PDB Sequence |
GEAPNQALLR
705 ILKETEFKKI715 KVLGSGAFGT725 VYKGLWIPEG735 EKVKIPVAIK745 ELREATSPKA 755 NKEILDEAYV765 MASVDNPHVC775 RLLGICLTST785 VQLITQLMPF795 GCLLDYVREH 805 KDNIGSQYLL815 NWCVQIAKGM825 NYLEDRRLVH835 RDLAARNVLV845 KTPQHVKITD 855 FGRAKLLGAE865 EGGKVPIKWM881 ALESILHRIY891 THQSDVWSYG901 VTVWELMTFG 911 SKPYDGIPAS921 EISSILEKGE931 RLPQPPICTI941 DVYMIMVKCW951 MIDADSRPKF 961 RELIIEFSKM971 ARDPQRYLVI981 QGDERMHLPS991 PTDSNFYRAL1001 MDEEDMDDVV 1011 DADEYLIPQ
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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 .YY3 or .YY32 or .YY33 or :3YY3;style chemicals stick;color identity;select .A:718 or .A:719 or .A:726 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:794 or .A:795 or .A:796 or .A:797 or .A:800 or .A:841 or .A:844; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 7K1H EGFR L858R/V948R in complex with osimertinib and allosteric inhibitor JBJ-09-063 | ||||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | Yes | [2] |
| PDB Sequence |
QALLRILKET
710 EFKKIKVLGS720 GAFGTVYKGL730 WIPEGEKVKI740 PVAIKELREA750 TSPKANKEIL 760 DEAYVMASVD770 NPHVCRLLGI780 CLTSTVQLIT790 QLMPFGCLLD800 YVREHKDNIG 810 SQYLLNWCVQ820 IAKGMNYLED830 RRLVHRDLAA840 RNVLVKTPQH850 VKITDFGRVP 877 IKWMALESIL887 HRIYTHQSDV897 WSYGVTVWEL907 MTFGSKPYDG917 IPASEISSIL 927 EKGERLPQPP937 ICTIDVYMIM947 RKCWMIDADS957 RPKFRELIIE967 FSKMARDPQR 977 YLVIQGDERM987 HLPSPTDSNF997 YRALMDEEDM1007 D
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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 .YY3 or .YY32 or .YY33 or :3YY3;style chemicals stick;color identity;select .B:718 or .B:719 or .B:720 or .B:721 or .B:726 or .B:743 or .B:745 or .B:790 or .B:791 or .B:792 or .B:793 or .B:794 or .B:796 or .B:797 or .B:800 or .B:804 or .B:841 or .B:842 or .B:844 or .B:854 or .B:855; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU718
3.664
GLY719
3.501
SER720
3.901
GLY721
4.790
VAL726
3.454
ALA743
3.666
LYS745
4.400
THR790
4.258
GLN791
3.429
LEU792
3.456
MET793
3.129
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| PDB ID: 4ZAU AZD9291 complex with wild type EGFR | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [3] |
| PDB Sequence |
APNQALLRIL
707 KETEFKKIKV717 LGSGAFGTVY727 KGLWIPEGEK737 VKIPVAIKEN756 KEILDEAYVM 766 ASVDNPHVCR776 LLGICLTSTV786 QLITQLMPFG796 CLLDYVREHK806 DNIGSQYLLN 816 WCVQIAKGMN826 YLEDRRLVHR836 DLAARNVLVK846 TPQHVKITDF856 GLAKLLEKEY 869 HAEKVPIKWM881 ALESILHRIY891 THQSDVWSYG901 VTVWELMTFG911 SKPYDGIPAS 921 EISSILEKGE931 RLPQPPICTI941 DVYMIMVKCW951 MIDADSRPKF961 RELIIEFSKM 971 ARDPQRYLVI981 QGDDDVVDAD1014 EYL
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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 .YY3 or .YY32 or .YY33 or :3YY3;style chemicals stick;color identity;select .A:718 or .A:719 or .A:726 or .A:728 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:794 or .A:795 or .A:796 or .A:797 or .A:800 or .A:844; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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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 | [4] |
| 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
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .YY3 or .YY32 or .YY33 or :3YY3;style chemicals stick;color identity;select .A:718 or .A:719 or .A:723 or .A:726 or .A:728 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:794 or .A:795 or .A:796 or .A:797 or .A:800 or .A:804 or .A:844 or .A:1001; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural Basis of AZD9291 Selectivity for EGFR T790M. J Med Chem. 2020 Aug 13;63(15):8502-8511. | ||||
| REF 2 | Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. doi:10.1038/s41467-022-30258-y. | ||||
| REF 3 | Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-544. | ||||
| REF 4 | CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation. Mol Cancer Ther. 2020 Nov;19(11):2288-2297. | ||||
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