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 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
EGFR_HUMAN
Ligand General Information  Top
Ligand Name 6-ethyl-3-[[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-[(3R)-1-prop-2-enoylpyrrolidin-3-yl]oxy-pyrazine-2-carboxamide Ligand Info
Canonical SMILES CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)OC5CCN(C5)C(=O)CCS
InChI 1S/C30H44N8O3S/c1-3-25-30(41-24-10-14-38(20-24)26(39)11-19-42)34-29(27(33-25)28(31)40)32-21-4-6-22(7-5-21)36-12-8-23(9-13-36)37-17-15-35(2)16-18-37/h4-7,23-24,42H,3,8-20H2,1-2H3,(H2,31,40)(H,32,34)/t24-/m1/s1
InChIKey TVWOOIFKLPBSKV-XMMPIXPASA-N
PubChem Compound ID 134686793
Drug Binding Sites of Target  Top
PDB ID: 5Y9T      Crystal Structure of EGFR T790M mutant in complex with naquotinib
Method X-ray diffraction Resolution 3.25 Å Mutation Yes [1]
PDB Sequence
EAPNQALLRI
706
LKETEFKKIK
716
VLGSGAFGTV
726
YKGLWIPEGE
736
KVKIPVAIKE
746

LRTSPKANKE
758
ILDEAYVMAS
768
VDNPHVCRLL
778
GICLTSTVQL
788
IMQLMPFGCL
798

LDYVREHKDN
808
IGSQYLLNWC
818
VQIAKGMNYL
828
EDRRLVHRDL
838
AARNVLVKTP
848

QHVKITDFGL
858
AKLLGAEEKE
868
YHAEGGKVPI
878
KWMALESILH
888
RIYTHQSDVW
898

SYGVTVWELM
908
TFGSKPYDGI
918
PASEISSILE
928
KGERLPQPPI
938
CTIDVYMIMV
948

KCWMIDADSR
958
PKFRELIIEF
968
SKMARDPQRY
978
LVIQGDMDDV
1010
VDADEYLIPQ
1020
Residue
Distance (Å)
LEU718
3.525
GLY719
4.873
VAL726
3.588
ALA743
3.394
LYS745
3.898
CYS775
4.733
MET790
3.220
GLN791
2.881
LEU792
3.666
Residue
Distance (Å)
MET793
2.818
PRO794
2.901
PHE795
4.363
GLY796
3.818
CYS797
1.831
ASP800
2.855
GLU804
4.009
ARG841
3.850
LEU844
3.232
PDB ID: 7LG8      EGFR (T79M/V948R) in complex with naquotinib and an allosteric inhibitor
Method X-ray diffraction Resolution 2.93 Å Mutation Yes [2]
PDB Sequence
ALLRILKETE
711
FKKIKVLGSG
721
AFGTVYKGLW
731
IPEGEKVKIP
741
VAIKELREAT
751

SPKANKEILD
761
EAYVMASVDN
771
PHVCRLLGIC
781
LTSTVQLIMQ
791
LMPFGCLLDY
801

VREHKDNIGS
811
QYLLNWCVQI
821
AKGMNYLEDR
831
RLVHRDLAAR
841
NVLVKTPQHV
851

KITDFGLAKV
876
PIKWMALESI
886
LHRIYTHQSD
896
VWSYGVTVWE
906
LMTFGSKPYD
916

GIPASEISSI
926
LEKGERLPQP
936
PICTIDVYMI
946
MRKCWMIDAD
956
SRPKFRELII
966

EFSKMARDPQ
976
RYLVIQGDEN
996
FYRALMDEED
1006
Residue
Distance (Å)
LEU718
3.412
GLY719
4.007
VAL726
4.108
ALA743
3.598
LYS745
4.465
MET790
3.342
GLN791
3.228
LEU792
3.207
MET793
2.877
PRO794
3.802
PHE795
4.180
Residue
Distance (Å)
GLY796
3.805
CYS797
1.740
LEU799
4.973
ASP800
2.993
GLU804
3.467
ARG841
3.864
LEU844
3.364
THR854
3.755
ASP855
3.594
MET1002
3.813
ASP1003
3.689
References  Top
REF 1 Pharmacological and Structural Characterizations of Naquotinib, a Novel Third-Generation EGFR Tyrosine Kinase Inhibitor, in EGFR-Mutated Non-Small Cell Lung Cancer. Mol Cancer Ther. 2018 Apr;17(4):740-750.
REF 2 Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. Nat Commun. 2022 May 9;13(1):2530.

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