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 T31186 Target Info
Target Name Eukaryotic initiation factor 4E (EIF4E)
Synonyms eIF4F 25 kDa subunit; eIF4E; eIF-4F 25 kDa subunit; eIF-4E; Eukaryotic translation initiation factor 4E; EIF4F; EIF4EL1
Target Type Literature-reported Target
Gene Name EIF4E
UniProt ID
IF4E_HUMAN
Ligand General Information  Top
Ligand Name 7-Methyl-Guanosine-5'-Triphosphate Ligand Info
Canonical SMILES CN1C=[N+](C2=C1C(=O)NC(=N2)N)C3C(C(C(O3)COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O)O
InChI 1S/C11H18N5O14P3/c1-15-3-16(8-5(15)9(19)14-11(12)13-8)10-7(18)6(17)4(28-10)2-27-32(23,24)30-33(25,26)29-31(20,21)22/h3-4,6-7,10,17-18H,2H2,1H3,(H6-,12,13,14,19,20,21,22,23,24,25,26)/p+1/t4-,6-,7-,10-/m1/s1
InChIKey DKVRNHPCAOHRSI-KQYNXXCUSA-O
PubChem Compound ID 135419182
Drug Binding Sites of Target  Top
PDB ID: 1IPC      CRYSTAL STRUCTURE OF EUKARYOTIC INITIATION FACTOR 4E COMPLEXED WITH 7-METHYL GTP
Method X-ray diffraction Resolution 2.00 Å Mutation No [1]
PDB Sequence
EVANPEHYIK
36
HPLQNRWALW
46
FFKNDKSKTW
56
QANLRLISKF
66
DTVEDFWALY
76

NHIQLSSNLM
86
PGCDYSLFKD
96
GIEPMWEDEK
106
NKRGGRWLIT
116
LNKQQRRSDL
126

DRFWLETLLC
136
LIGESFDDYS
146
DDVCGAVVNV
156
RAKGDKIAIW
166
TTECENREAV
176

THIGRVYKER
186
LGLPPKIVIG
196
YQSHADTATT
211
KNRFVV
Residue
Distance (Å)
TRP56
3.349
ASP90
4.671
PRO100
4.311
MET101
3.049
TRP102
2.655
GLU103
2.845
Residue
Distance (Å)
ARG112
4.479
ASN155
4.060
ARG157
2.871
LYS162
2.855
TRP166
4.004
PDB ID: 5T46      Crystal structure of the human eIF4E-eIF4G complex
Method X-ray diffraction Resolution 1.53 Å Mutation No [2]
PDB Sequence
PEHYIKHPLQ
40
NRWALWFFKN
50
DKSKTWQANL
60
RLISKFDTVE
70
DFWALYNHIQ
80

LSSNLMPGCD
90
YSLFKDGIEP
100
MWEDEKNKRG
110
GRWLITLNKQ
120
QRRSDLDRFW
130

LETLLCLIGE
140
SFDDYSDDVC
150
GAVVNVRAKG
160
DKIAIWTTEC
170
ENREAVTHIG
180

RVYKERLGLP
190
PKIVIGYQSH
200
ADTATK
Residue
Distance (Å)
TRP56
2.728
GLN57
4.504
ASP90
4.830
PRO100
4.067
MET101
2.462
TRP102
1.958
GLU103
1.665
ARG112
4.115
Residue
Distance (Å)
VAL153
4.944
ASN155
3.934
ARG157
1.994
LYS162
1.872
TRP166
2.923
THR203
4.959
ALA204
4.806
LYS206
2.692
PDB ID: 7MEU      A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders
Method X-ray diffraction Resolution 1.91 Å Mutation No [3]
PDB Sequence
YIKHPLQNRW
43
ALWFFKNDKS
53
KTWQANLRLI
63
SKFDTVEDFW
73
ALYNHIQLSS
83

NLMPGCDYSL
93
FKDGIEPMWE
103
DEKNKRGGRW
113
LITLNKQQRR
123
SDLDRFWLET
133

LLCLIGESFD
143
DYSDDVCGAV
153
VNVRAKGDKI
163
AIWTTECENR
173
EAVTHIGRVY
183

KERLGLPPKI
193
VIGYQSHADT
203
ATKSGSTTKN
213
RFVV
Residue
Distance (Å)
ASN50
4.426
TRP56
2.939
GLN57
4.514
ASP90
4.442
PRO100
4.313
MET101
2.442
TRP102
1.887
GLU103
2.650
Residue
Distance (Å)
ARG112
4.029
ASN155
4.005
ARG157
1.800
LYS159
3.304
LYS162
1.822
TRP166
3.184
LYS206
3.198
SER209
4.606
PDB ID: 4TPW      The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G
Method X-ray diffraction Resolution 1.50 Å Mutation No [4]
PDB Sequence
HYIKHPLQNR
42
WALWFFKNDK
52
SKTWQANLRL
62
ISKFDTVEDF
72
WALYNHIQLS
82

SNLMPGCDYS
92
LFKDGIEPMW
102
EDEKNKRGGR
112
WLITLNKQQR
122
RSDLDRFWLE
132

TLLCLIGESF
142
DDYSDDVCGA
152
VVNVRAKGDK
162
IAIWTTECEN
172
REAVTHIGRV
182

YKERLGLPPK
192
IVIGYQSHAD
202
TATKSGSTTK
212
NRFVV
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .MGP or .MGP2 or .MGP3 or :3MGP;style chemicals stick;color identity;select .A:50 or .A:52 or .A:56 or .A:57 or .A:90 or .A:100 or .A:101 or .A:102 or .A:103 or .A:112 or .A:155 or .A:157 or .A:159 or .A:162 or .A:166 or .A:203 or .A:204 or .A:206 or .A:207 or .A:208 or .A:209; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
ASN50
4.306
LYS52
4.722
TRP56
2.703
GLN57
3.380
ASP90
4.527
PRO100
4.503
MET101
2.573
TRP102
1.965
GLU103
2.352
ARG112
3.861
ASN155
3.997
Residue
Distance (Å)
ARG157
1.961
LYS159
4.301
LYS162
1.878
TRP166
2.892
THR203
4.693
ALA204
4.504
LYS206
3.922
SER207
2.809
GLY208
2.637
SER209
3.763
PDB ID: 5ZJY      Stapled-peptides tailored against initiation of translation
Method X-ray diffraction Resolution 1.59 Å Mutation No [5]
PDB Sequence
HYIKHPLQNR
42
WALWFFKNDK
52
SKTWQANLRL
62
ISKFDTVEDF
72
WALYNHIQLS
82

SNLMPGCDYS
92
LFKDGIEPMW
102
EDEKNKRGGR
112
WLITLNKQQR
122
RSDLDRFWLE
132

TLLCLIGESF
142
DDYSDDVCGA
152
VVNVRAKGDK
162
IAIWTTECEN
172
REAVTHIGRV
182

YKERLGLPPK
192
IVIGYQSHAD
202
TATTKNRFVV
217
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .MGP or .MGP2 or .MGP3 or :3MGP;style chemicals stick;color identity;select .A:56 or .A:57 or .A:100 or .A:101 or .A:102 or .A:103 or .A:112 or .A:155 or .A:157 or .A:162 or .A:166; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
TRP56
3.276
GLN57
4.446
PRO100
4.392
MET101
3.169
TRP102
2.776
GLU103
2.784
Residue
Distance (Å)
ARG112
4.857
ASN155
4.511
ARG157
2.690
LYS162
2.625
TRP166
4.279
PDB ID: 5ZK9      Stapled-peptides tailored against initiation of translation
Method X-ray diffraction Resolution 1.76 Å Mutation No [5]
PDB Sequence
PEHYIKHPLQ
40
NRWALWFFKN
50
DKSKTWQANL
60
RLISKFDTVE
70
DFWALYNHIQ
80

LSSNLMPGCD
90
YSLFKDGIEP
100
MWEDEKNKRG
110
GRWLITLNKQ
120
QRRSDLDRFW
130

LETLLCLIGE
140
SFDDYSDDVC
150
GAVVNVRAKG
160
DKIAIWTTEC
170
ENREAVTHIG
180

RVYKERLGLP
190
PKIVIGYQSH
200
ADTATKTKNR
214
FVV
Click to Show 3D Structure of This Binding Site
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Residue
Distance (Å)
TRP56
3.230
ASP90
4.377
PRO100
4.472
MET101
3.172
TRP102
2.771
GLU103
2.625
Residue
Distance (Å)
ARG112
4.678
ASN155
4.061
ARG157
2.655
LYS162
2.668
TRP166
4.315
PDB ID: 3AM7      Crystal structure of the ternary complex of eIF4E-M7GTP-4EBP2 peptide
Method X-ray diffraction Resolution 2.20 Å Mutation No [6]
PDB Sequence
EVANPEHYIK
36
HPLQNRWALW
46
FFKNDKSKTW
56
QANRLISKFD
67
TVEDFWALYN
77

HIQLSSNLMP
87
GCDYSLFKDG
97
IEPMWEDEKN
107
KRGGRWLITL
117
NKQQRRSDLD
127

RFWLETLLCL
137
IGESFDDYSD
147
DVCGAVVNVR
157
AKGDKIAIWT
167
TECENREAVT
177

HIGRVYKERL
187
GLPPKIVIGY
197
QSHADTATKS
207
GSTTKNRFVV
217
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .MGP or .MGP2 or .MGP3 or :3MGP;style chemicals stick;color identity;select .A:56 or .A:90 or .A:100 or .A:101 or .A:102 or .A:103 or .A:112 or .A:155 or .A:157 or .A:159 or .A:162 or .A:166; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
TRP56
3.426
ASP90
4.434
PRO100
4.194
MET101
2.943
TRP102
2.632
GLU103
2.819
Residue
Distance (Å)
ARG112
4.534
ASN155
4.075
ARG157
2.880
LYS159
2.840
LYS162
2.923
TRP166
4.101
References  Top
REF 1 Crystal structures of 7-methylguanosine 5'-triphosphate (m(7)GTP)- and P(1)-7-methylguanosine-P(3)-adenosine-5',5'-triphosphate (m(7)GpppA)-bound human full-length eukaryotic initiation factor 4E: biological importance of the C-terminal flexible region. Biochem J. 2002 Mar 15;362(Pt 3):539-44.
REF 2 The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation. Mol Cell. 2016 Nov 3;64(3):467-479.
REF 3 A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders. Eur J Med Chem. 2021 Jul 5;219:113435.
REF 4 Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):E3187-95.
REF 5 Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein. Chem Sci. 2019 Jan 7;10(8):2489-2500.
REF 6 Structural scaffold for eIF4E binding selectivity of 4E-BP isoforms: crystal structure of eIF4E binding region of 4E-BP2 and its comparison with that of 4E-BP1. J Pept Sci. 2011 Sep;17(9):650-7.

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