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 N-[(3R,4R)-4-fluoro-1-[6-[(3-methoxy-1-methylpyrazol-4-yl)amino]-9-methylpurin-2-yl]pyrrolidin-3-yl]propanamide Ligand Info
Canonical SMILES CCC(=O)NC1CN(CC1F)C2=NC(=C3C(=N2)N(C=N3)C)NC4=CN(N=C4OC)C
InChI 1S/C18H24FN9O2/c1-5-13(29)21-11-8-28(6-10(11)19)18-23-15(14-16(24-18)26(2)9-20-14)22-12-7-27(3)25-17(12)30-4/h7,9-11H,5-6,8H2,1-4H3,(H,21,29)(H,22,23,24)/t10-,11-/m1/s1
InChIKey XWNKXCUQRQRAFF-GHMZBOCLSA-N
PubChem Compound ID 137348700
Drug Binding Sites of Target  Top
PDB ID: 6Z4D      Crystal Structure of EGFR-T790M/V948R in Complex with Mavelertinib and EAI001
Method X-ray diffraction Resolution 2.00 Å Mutation Yes [1]
PDB Sequence
QALLRILKET
710
EFKKIKVLGS
720
GAFGTVYKGL
730
WIPEGEKVKI
740
PVAIKELREA
750

TSANKEILDE
762
AYVMASVDNP
772
HVCRLLGICL
782
TSTVQLIMQL
792
MPFGCLLDYV
802

REHKDNIGSQ
812
YLLNWCVQIA
822
KGMNYLEDRR
832
LVHRDLAARN
842
VLVKTPQHVK
852

ITDFGLAKLL
862
VPIKWMALES
885
ILHRIYTHQS
895
DVWSYGVTVW
905
ELMTFGSKPY
915

DGIPASEISS
925
ILEKGERLPQ
935
PPICTIDVYM
945
IMRKCWMIDA
955
DSRPKFRELI
965

IEFSKMARDP
975
QRYLVIQGD
Residue
Distance (Å)
LEU718
3.534
GLY719
3.027
SER720
4.253
PHE723
4.175
VAL726
3.532
LYS728
4.598
ALA743
3.429
MET790
3.575
GLN791
3.260
LEU792
3.672
Residue
Distance (Å)
MET793
2.510
PRO794
3.320
PHE795
4.793
GLY796
3.483
CYS797
1.798
LEU799
4.280
ASP800
3.335
ARG841
3.466
LEU844
3.351
THR854
4.197
PDB ID: 7JXI      EGFR kinase (T790M/V948R) in complex with PF-06747775
Method X-ray diffraction Resolution 3.00 Å Mutation Yes [2]
PDB Sequence
ALLRILKETE
711
FKKIKVLGSG
721
AFGTVYKGLW
731
IPEGEKVKIP
741
VAIKELREAT
751

ANKEILDEAY
764
VMASVDNPHV
774
CRLLGICLTS
784
TVQLIMQLMP
794
FGCLLDYVRE
804

HKDNIGSQYL
814
LNWCVQIAKG
824
MNYLEDRRLV
834
HRDLAARNVL
844
VKTPQHVKIT
854

DFGLAKLLVP
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
YRALMDEED
Residue
Distance (Å)
LEU718
3.745
GLY719
3.665
SER720
3.873
GLY721
4.169
GLY724
4.871
VAL726
3.314
LYS728
4.482
ALA743
3.496
LYS745
4.071
MET790
3.483
GLN791
3.067
Residue
Distance (Å)
LEU792
3.626
MET793
2.849
PRO794
3.870
PHE795
4.859
GLY796
3.400
CYS797
1.765
LEU799
4.987
ASP800
3.503
ARG841
3.367
LEU844
3.583
THR854
4.625
PDB ID: 5UGC      Crystal structure of the EGFR kinase domain (L858R, T790M, V948R) in complex with a covalent inhibitor N-[(3R,4R)-4-fluoro-1-{6-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-9-methyl-9H-purin-2-yl}pyrrolidin-3-yl]propanamide
Method X-ray diffraction Resolution 1.58 Å Mutation Yes [3]
PDB Sequence
ALLRILKETE
711
FKKIKVLGSG
721
AFGTVYKGLW
731
IPEGEKVKIP
741
VAIKELRPKA
755

NKEILDEAYV
765
MASVDNPHVC
775
RLLGICLTST
785
VQLIMQLMPF
795
GCLLDYVREH
805

KDNIGSQYLL
815
NWCVQIAKGM
825
NYLEDRRLVH
835
RDLAARNVLV
845
KTPQHVKITD
855

FGRAKLLGAE
865
EKEYHAEGGK
875
VPIKWMALES
885
ILHRIYTHQS
895
DVWSYGVTVW
905

ELMTFGSKPY
915
DGIPASEISS
925
ILEKGERLPQ
935
PPICTIDVYM
945
IMRKCWMIDA
955

DSRPKFRELI
965
IEFSKMARDP
975
QRYLVIQGDE
985
Residue
Distance (Å)
LEU718
3.495
GLY719
3.186
SER720
3.879
PHE723
3.817
VAL726
3.730
LYS728
4.571
ALA743
3.321
CYS775
3.993
MET790
3.784
GLN791
3.117
LEU792
3.712
Residue
Distance (Å)
MET793
2.908
PRO794
3.137
PHE795
4.587
GLY796
3.317
CYS797
1.810
LEU799
4.285
ASP800
3.567
ARG841
3.506
LEU844
3.302
THR854
4.104
PHE856
3.445
References  Top
REF 1 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 2 Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors. doi:10.1038/s41467-022-30258-y.
REF 3 Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR. J Med Chem. 2017 Apr 13;60(7):3002-3019.

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