Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
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
EGFR_HUMAN
Ligand General Information  Top
Ligand Name AMP-PNP Ligand Info
Canonical SMILES C1=NC(=C2C(=N1)N(C=N2)C3C(C(C(O3)COP(=O)(O)OP(=O)(NP(=O)(O)O)O)O)O)N
InChI 1S/C10H17N6O12P3/c11-8-5-9(13-2-12-8)16(3-14-5)10-7(18)6(17)4(27-10)1-26-31(24,25)28-30(22,23)15-29(19,20)21/h2-4,6-7,10,17-18H,1H2,(H,24,25)(H2,11,12,13)(H4,15,19,20,21,22,23)/t4-,6-,7-,10-/m1/s1
InChIKey PVKSNHVPLWYQGJ-KQYNXXCUSA-N
PubChem Compound ID 33113
Drug Binding Sites of Target  Top
PDB ID: 3VJN      Crystal structure of the mutated EGFR kinase domain (G719S/T790M) in complex with AMPPNP.
Method X-ray diffraction Resolution 2.34 Å Mutation Yes [1]
PDB Sequence
EAPNQALLRI
706
LKETEFKKIK
716
VLSSGTVYKG
729
LWIPEGEKVK
739
IPVAIKELEA
750

TSPKANKEIL
760
DEAYVMASVD
770
NPHVCRLLGI
780
CLTSTVQLIM
790
QLMPFGCLLD
800

YVREHKDNIG
810
SQYLLNWCVQ
820
IAKGMNYLED
830
RRLVHRDLAA
840
RNVLVKTPQH
850

VKITDFGLAK
860
LLGAEEKEYH
870
AEGGKVPIKW
880
MALESILHRI
890
YTHQSDVWSY
900

GVTVWELMTF
910
GSKPYDGIPA
920
SEISSILEKG
930
ERLPQPPICT
940
IDVYMIMVKC
950

WMIDADSRPK
960
FRELIIEFSK
970
MARDPQRYLV
980
IQGDDMDDVV
1011
DADEYLI
Residue
Distance (Å)
LEU718
4.065
SER719
3.529
VAL726
3.803
ALA743
3.425
LYS745
3.030
CYS775
4.900
MET790
3.157
GLN791
2.959
Residue
Distance (Å)
LEU792
3.904
MET793
2.953
GLY796
4.730
CYS797
3.799
ARG841
4.917
ASN842
4.434
LEU844
3.625
ASP855
3.199
PDB ID: 7JXQ      EGFR kinase (T790M/V948R) in complex with allosteric inhibitor JBJ-09-063
Method X-ray diffraction Resolution 1.83 Å Mutation Yes [2]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
KLLGAEVPIK
879
WMALESILHR
889
IYTHQSDVWS
899
YGVTVWELMT
909

FGSKPYDGIP
919
ASEISSILEK
929
GERLPQPPIC
939
TIDVYMIMRK
949
CWMIDADSRP
959

KFRELIIEFS
969
KMARDPQRYL
979
VIQGDERMHL
989
PSPTDSNFYR
999
ALMDEEDM
Residue
Distance (Å)
LEU718
3.794
GLY719
3.569
SER720
3.529
GLY721
3.020
ALA722
3.124
PHE723
4.621
GLY724
3.935
VAL726
3.401
ALA743
3.484
LYS745
2.711
MET790
3.409
Residue
Distance (Å)
GLN791
2.883
LEU792
3.852
MET793
2.934
GLY796
4.544
CYS797
3.277
ASP800
4.526
ASP837
2.578
ARG841
2.857
ASN842
3.033
LEU844
3.511
ASP855
2.748
PDB ID: 5X2A      Crystal structure of EGFR 696-1022 T790M/V948R in complex with SKLB(3)
Method X-ray diffraction Resolution 1.85 Å Mutation Yes [3]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
KLLVPIKWMA
882
LESILHRIYT
892
HQSDVWSYGV
902
TVWELMTFGS
912

KPYDGIPASE
922
ISSILEKGER
932
LPQPPICTID
942
VYMIMRKCWM
952
IDADSRPKFR
962

ELIIEFSKMA
972
RDPQRYLVIQ
982
GDERMHLPSP
992
TDSNFYRALM
1002
DEEDMVV
Residue
Distance (Å)
LEU718
4.968
GLY719
3.585
SER720
3.430
GLY721
3.176
ALA722
2.948
PHE723
3.882
GLY724
3.769
Residue
Distance (Å)
VAL726
3.068
LYS745
2.980
ASP837
2.484
ARG841
2.758
ASN842
2.692
ASP855
2.369
PDB ID: 4ZSE      Crystal structure of EGFR 696-1022 T790M/V948R, crystal form II
Method X-ray diffraction Resolution 1.97 Å Mutation Yes [4]
PDB Sequence
PNQALLRILK
708
ETEFKKIKVL
718
GSGAFGTVYK
728
GLWIPEGEKV
738
KIPVAIKELR
748

EATSPKANKE
758
ILDEAYVMAS
768
VDNPHVCRLL
778
GICLTSTVQL
788
IMQLMPFGCL
798

LDYVREHKDN
808
IGSQYLLNWC
818
VQIAKGMNYL
828
EDRRLVHRDL
838
AARNVLVKTP
848

QHVKITDFGL
858
AKLLKVPIKW
880
MALESILHRI
890
YTHQSDVWSY
900
GVTVWELMTF
910

GSKPYDGIPA
920
SEISSILEKG
930
ERLPQPPICT
940
IDVYMIMRKC
950
WMIDADSRPK
960

FRELIIEFSK
970
MARDPQRYLV
980
IQGDERMHLP
990
SPTDSNFYRA
1000
LMDEEDM
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .A:718 or .A:719 or .A:720 or .A:721 or .A:722 or .A:723 or .A:724 or .A:725 or .A:726 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:796 or .A:797 or .A:800 or .A:837 or .A:841 or .A:842 or .A:844 or .A:855; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
3.497
GLY719
3.647
SER720
3.653
GLY721
3.159
ALA722
3.111
PHE723
4.221
GLY724
3.433
THR725
4.902
VAL726
3.330
ALA743
3.529
LYS745
2.912
MET790
3.937
Residue
Distance (Å)
GLN791
3.057
LEU792
3.833
MET793
2.955
GLY796
4.633
CYS797
3.467
ASP800
4.607
ASP837
2.648
ARG841
2.879
ASN842
2.960
LEU844
3.448
ASP855
2.745
PDB ID: 7JXP      EGFR kinase (T790M/V948R) in complex with osimertinib and JBJ-04-125-02
Method X-ray diffraction Resolution 2.16 Å Mutation Yes [5]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
KLVPIKWMAL
883
ESILHRIYTH
893
QSDVWSYGVT
903
VWELMTFGSK
913

PYDGIPASEI
923
SSILEKGERL
933
PQPPICTIDV
943
YMIMRKCWMI
953
DADSRPKFRE
963

LIIEFSKMAR
973
DPQRYLVIQG
983
DERMHLPSPT
993
DSNFYRALMD
1003
EEDM
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .D:718 or .D:719 or .D:720 or .D:721 or .D:722 or .D:723 or .D:724 or .D:725 or .D:726 or .D:743 or .D:745 or .D:790 or .D:791 or .D:792 or .D:793 or .D:796 or .D:797 or .D:800 or .D:837 or .D:841 or .D:842 or .D:844 or .D:855; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
3.704
GLY719
3.437
SER720
3.631
GLY721
3.208
ALA722
2.714
PHE723
4.762
GLY724
3.673
THR725
4.804
VAL726
3.158
ALA743
3.561
LYS745
3.178
MET790
3.439
Residue
Distance (Å)
GLN791
3.019
LEU792
3.758
MET793
3.119
GLY796
4.601
CYS797
3.152
ASP800
4.074
ASP837
2.536
ARG841
2.665
ASN842
2.782
LEU844
3.325
ASP855
2.629
PDB ID: 7JXM      EGFR kinase (T790M/V948R) in complex with osimertinib and EAI045
Method X-ray diffraction Resolution 2.19 Å Mutation Yes [5]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLV
876
PIKWMALESI
886
LHRIYTHQSD
896
VWSYGVTVWE
906
LMTFGSKPYD
916

GIPASEISSI
926
LEKGERLPQP
936
PICTIDVYMI
946
MRKCWMIDAD
956
SRPKFRELII
966

EFSKMARDPQ
976
RYLVIQGDER
986
MHLPSPTDSN
996
FYRALMDEED
1006
M
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .D:718 or .D:719 or .D:720 or .D:721 or .D:722 or .D:723 or .D:724 or .D:726 or .D:743 or .D:745 or .D:790 or .D:791 or .D:792 or .D:793 or .D:796 or .D:797 or .D:800 or .D:837 or .D:841 or .D:842 or .D:844 or .D:855; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
3.779
GLY719
3.693
SER720
3.456
GLY721
3.061
ALA722
2.985
PHE723
4.900
GLY724
3.498
VAL726
3.350
ALA743
3.545
LYS745
3.365
MET790
3.280
Residue
Distance (Å)
GLN791
3.030
LEU792
3.869
MET793
3.019
GLY796
4.397
CYS797
3.361
ASP800
4.284
ASP837
2.645
ARG841
2.559
ASN842
3.143
LEU844
3.381
ASP855
2.757
PDB ID: 7LTX      EGFR (T790M/V948R) in complex with quinazolinone allosteric inhibitor
Method X-ray diffraction Resolution 2.30 Å Mutation Yes [6]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
VPIKWMALES
885
ILHRIYTHQS
895
DVWSYGVTVW
905
ELMTFGSKPY
915

DGIPASEISS
925
ILEKGERLPQ
935
PPICTIDVYM
945
IMRKCWMIDA
955
DSRPKFRELI
965

IEFSKMARDP
975
QRYLVIQGDE
985
RMHLPSPTDS
995
NFYRALMDEE
1005
DM
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .A:718 or .A:719 or .A:720 or .A:721 or .A:722 or .A:723 or .A:724 or .A:725 or .A:726 or .A:743 or .A:745 or .A:790 or .A:791 or .A:792 or .A:793 or .A:796 or .A:797 or .A:800 or .A:837 or .A:841 or .A:842 or .A:844 or .A:855; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
3.798
GLY719
3.698
SER720
3.575
GLY721
3.285
ALA722
3.200
PHE723
4.488
GLY724
3.600
THR725
4.882
VAL726
3.400
ALA743
3.488
LYS745
2.828
MET790
3.503
Residue
Distance (Å)
GLN791
2.865
LEU792
3.849
MET793
3.029
GLY796
4.432
CYS797
3.200
ASP800
4.068
ASP837
2.648
ARG841
2.930
ASN842
2.842
LEU844
3.625
ASP855
2.846
PDB ID: 7JXK      EGFR kinase (T790M/V948R) in complex with PF-06747775 and JBJ-04-125-02
Method X-ray diffraction Resolution 3.10 Å Mutation Yes [5]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
MQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
KLVPIKWMAL
883
ESILHRIYTH
893
QSDVWSYGVT
903
VWELMTFGSK
913

PYDGIPASEI
923
SSILEKGERL
933
PQPPICTIDV
943
YMIMRKCWMI
953
DADSRPKFRE
963

LIIEFSKMAR
973
DPQRYLVIQG
983
DERMHLPSPT
993
DSNFYRALMD
1003
EEDM
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .D:718 or .D:719 or .D:720 or .D:721 or .D:722 or .D:723 or .D:724 or .D:726 or .D:743 or .D:745 or .D:790 or .D:791 or .D:792 or .D:793 or .D:796 or .D:797 or .D:800 or .D:837 or .D:841 or .D:842 or .D:844 or .D:855; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
4.034
GLY719
3.380
SER720
3.454
GLY721
3.210
ALA722
4.122
PHE723
3.571
GLY724
3.313
VAL726
3.145
ALA743
3.272
LYS745
3.100
MET790
3.787
Residue
Distance (Å)
GLN791
2.923
LEU792
3.763
MET793
3.257
GLY796
4.602
CYS797
3.186
ASP800
4.391
ASP837
3.054
ARG841
2.253
ASN842
2.413
LEU844
3.753
ASP855
3.005
PDB ID: 6WAK      A crystal structure of EGFR(T790M/V948R) in complex with LN3754
Method X-ray diffraction Resolution 2.40 Å Mutation Yes [7]
PDB Sequence
QALLRILKET
710
EFKKIKVLGS
720
GAFGTVYKGL
730
WIPEGEKVKI
740
PVAIKELREA
750

KANKEILDEA
763
YVMASVDNPH
773
VCRLLGICLT
783
STVQLIMQLM
793
PFGCLLDYVR
803

EHKDNIGSQY
813
LLNWCVQIAK
823
GMNYLEDRRL
833
VHRDLAARNV
843
LVKTPQHVKI
853

TDFGLAKLVP
877
IKWMALESIL
887
HRIYTHQSDV
897
WSYGVTVWEL
907
MTFGSKPYDG
917

IPASEISSIL
927
EKGERLPQPP
937
ICTIDVYMIM
947
RKCWMIDADS
957
RPKFRELIIE
967

FSKMARDPQR
977
YLVIQGDERM
987
HLPSPTDSNF
997
YRALMDEEDM
1007
DDVVDAD
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ANP or .ANP2 or .ANP3 or :3ANP;style chemicals stick;color identity;select .D:718 or .D:719 or .D:720 or .D:721 or .D:722 or .D:723 or .D:724 or .D:725 or .D:726 or .D:743 or .D:745 or .D:790 or .D:791 or .D:792 or .D:793 or .D:796 or .D:797 or .D:800 or .D:837 or .D:841 or .D:842 or .D:844 or .D:854 or .D:855; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
LEU718
3.460
GLY719
3.570
SER720
3.593
GLY721
3.432
ALA722
3.176
PHE723
3.581
GLY724
3.658
THR725
4.870
VAL726
3.387
ALA743
3.365
LYS745
2.817
MET790
3.950
Residue
Distance (Å)
GLN791
3.078
LEU792
3.945
MET793
3.276
GLY796
4.496
CYS797
3.226
ASP800
4.367
ASP837
2.806
ARG841
3.086
ASN842
2.892
LEU844
3.549
THR854
4.822
ASP855
2.838
References  Top
REF 1 Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene. 2013 Jan 3;32(1):27-38.
REF 2 An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer. Nat Cancer. 2022 Apr;3(4):402-417.
REF 3 Structural insights into drug development strategy targeting EGFR T790M/C797S. Oncotarget. 2018 Jan 10;9(17):13652-13665.
REF 4 Ibrutinib Selectively and Irreversibly Targets EGFR-mutant non-Small Cell Lung Cancer Cells
REF 5 Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. doi:10.1038/s41467-022-30258-y.
REF 6 Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC. Bioorg Med Chem Lett. 2022 Jul 15;68:128718.
REF 7 Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. J Med Chem. 2022 Jan 27;65(2):1370-1383.

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