Target Information

Target General Information

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Target ID

T31186 (Former ID: TTDI00074)

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

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Gene Name

EIF4E

Target Type

Literature-reported target

[1]

Function

Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression. In the CYFIP1-EIF4E-FMR1 complex this subunit mediates the binding to the mRNA cap. Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures.

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UniProt ID

IF4E_HUMAN

Sequence

MATVEPETTPTPNPPTTEEEKTESNQEVANPEHYIKHPLQNRWALWFFKNDKSKTWQANL
RLISKFDTVEDFWALYNHIQLSSNLMPGCDYSLFKDGIEPMWEDEKNKRGGRWLITLNKQ
QRRSDLDRFWLETLLCLIGESFDDYSDDVCGAVVNVRAKGDKIAIWTTECENREAVTHIG
RVYKERLGLPPKIVIGYQSHADTATKSGSTTKNRFVV

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3D Structure

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PDB

HIT2.0 ID

T77A47

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: 7-Methyl-Gpppa

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF EUKARYOTIC INITIATION FACTOR 4E COMPLEXED WITH 7-METHYL GPPPA

PDB:1IPB

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[2]

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

YQSHADTATK

²⁰⁶

SGSTTKNRFV

²¹⁶

Residue

Distance (Å)

TRP56

3.516

GLN57

3.106

ASP90

4.527

PRO100

4.311

MET101

3.064

TRP102

2.739

GLU103

2.827

ARG112

4.737

ASN155

4.294

ARG157

2.763

LYS162

2.860

Residue

Distance (Å)

TRP166

4.042

THR203

3.799

ALA204

3.335

THR205

3.020

LYS206

3.313

SER207

3.169

GLY208

4.472

SER209

4.380

THR210

4.838

THR211

4.753

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Ligand Name: 7-Methyl-Guanosine-5'-Triphosphate

Ligand Info

Structure Description

The co-complex structure of the translation initiation factor eIF4E with the inhibitor 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G

PDB:4TPW

Method

X-ray diffraction

Resolution

1.50 Å

Mutation

[3]

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

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

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Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
HIF-1 signaling pathway	hsa04066	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
mTOR signaling pathway	hsa04150	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Insulin signaling pathway	hsa04910	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

References

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REF 1

Signalling to eIF4E in cancer. Biochem Soc Trans. 2015 Oct;43(5):763-72.

REF 2

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 3

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.

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