Target Information

Target General Information

Target ID

T41119 (Former ID: TTDNR00715)

Target Name

Early response protein NAK1 (NR4A1)

Synonyms

Testicular receptor 3; ST-59; Orphan nuclear receptor TR3; Orphan nuclear receptor HMR; Nur77; Nuclear receptor subfamily 4 group A member 1; Nuclear hormone receptor NUR/77; NAK1; GFRP1

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Gene Name

NR4A1

Target Type

Literature-reported target

[1]

Function

May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3'. May inhibit NF-kappa-B transactivation of IL2. Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation. Plays a role in the vascular response to injury. Orphan nuclear receptor.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

NR4A1_HUMAN

Sequence

MPCIQAQYGTPAPSPGPRDHLASDPLTPEFIKPTMDLASPEAAPAAPTALPSFSTFMDGY
TGEFDTFLYQLPGTVQPCSSASSSASSTSSSSATSPASASFKFEDFQVYGCYPGPLSGPV
DEALSSSGSDYYGSPCSAPSPSTPSFQPPQLSPWDGSFGHFSPSQTYEGLRAWTEQLPKA
SGPPQPPAFFSFSPPTGPSPSLAQSPLKLFPSQATHQLGEGESYSMPTAFPGLAPTSPHL
EGSGILDTPVTSTKARSGAPGGSEGRCAVCGDNASCQHYGVRTCEGCKGFFKRTVQKNAK
YICLANKDCPVDKRRRNRCQFCRFQKCLAVGMVKEVVRTDSLKGRRGRLPSKPKQPPDAS
PANLLTSLVRAHLDSGPSTAKLDYSKFQELVLPHFGKEDAGDVQQFYDLLSGSLEVIRKW
AEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFG
DWIDSILAFSRSLHSLLVDVPAFACLSALVLITDRHGLQEPRRVEELQNRIASCLKEHVA
AVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKIFMDTLPF

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3D Structure

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AlphaFold

HIT2.0 ID

T25C2G

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: Ethyl (2,3,4-Trimethoxy-6-Octanoylphenyl)acetate

Ligand Info

Structure Description

Crystal Structure of Human Nur77 Ligand-binding Domain in Complex with Ethyl 2-[2,3,4 trimethoxy-6(1-octanoyl)phenyl]acetate

PDB:3V3Q

Method

X-ray diffraction

Resolution

2.22 Å

Mutation

[2]

PDB Sequence

DAPANLLTSL

³⁷

VRAHLDSGPS

⁴⁷

TAKLDYSKFQ

⁵⁷

ELVLPHFGKE

⁶⁷

DAGDVQQFYD

⁷⁷

LLSGSLEVIR

⁸⁷

KWAEKIPGFA

⁹⁷

ELSPADQDLL

¹⁰⁷

LESAFLELFI

¹¹⁷

LRLAYRSKPG

¹²⁷

EGKLIFCSGL

¹³⁷

VLHRLQCARG

¹⁴⁷

FGDWIDSILA

¹⁵⁷

FSRSLHSLLV

¹⁶⁷

DVPAFACLSA

¹⁷⁷

LVLITDRHGL

¹⁸⁷

QEPRRVEELQ

¹⁹⁷

NRIASCLKEH

²⁰⁷

VAAVAPASCL

²²¹

SRLLGKLPEL

²³¹

RTLCTQGLQR

²⁴¹

IFYLKLEDLV

²⁵¹

PPPPIIDKIF

²⁶¹

MDTLPFL

Residue

Distance (Å)

HIS41

3.303

LEU42

3.409

GLY45

4.819

PRO46

2.792

LEU51

4.940

GLU109

2.853

SER110

2.855

ALA111

3.330

PHE112

3.270

LEU113

2.398

GLU114

2.644

LEU115

4.982

ARG119

4.454

TYR122

2.795

ARG123

2.658

LYS125

2.811

ILE132

4.990

LEU162

2.895

Residue

Distance (Å)

HIS163

3.181

SER164

4.959

LEU165

4.216

LEU166

3.479

VAL167

2.779

VAL169

3.401

ARG184

4.142

LEU231

4.481

ARG232

3.024

THR233

4.896

CYS235

2.705

THR236

3.290

LEU239

3.193

ILE260

3.040

PHE261

3.943

ASP263

4.768

THR264

2.212

Ligand Name: 1-(3,4,5-Trihydroxyphenyl)nonan-1-one

Ligand Info

Structure Description

Crystal Structure of Human Nur77 Ligand-binding Domain in Complex with THPN

PDB:4JGV

Method

X-ray diffraction

Resolution

3.01 Å

Mutation

[3]

PDB Sequence

ANLLTSLVRA

³⁷¹

HLDSGPSTAK

³⁸¹

LDYSKFQELV

³⁹¹

LPHFGKEDAG

⁴⁰¹

DVQQFYDLLS

⁴¹¹

GSLEVIRKWA

⁴²¹

EKIPGFAELS

⁴³¹

PADQDLLLES

⁴⁴¹

AFLELFILRL

⁴⁵¹

AYRSKPGEGK

⁴⁶¹

LIFCSGLVLH

⁴⁷¹

RLQCARGFGD

⁴⁸¹

WIDSILAFSR

⁴⁹¹

SLHSLLVDVP

⁵⁰¹

AFACLSALVL

⁵¹¹

ITDRHGLQEP

⁵²¹

RRVEELQNRI

⁵³¹

ASCLKEHVAA

⁵⁴¹

VAEPPALSRL

⁵⁵⁵

LGKLPELRTL

⁵⁶⁵

CTQGLQRIFY

⁵⁷⁵

LKLEDLVPPP

⁵⁸⁵

PIIDKIFMDT

⁵⁹⁵

LPF

Residue

Distance (Å)

GLU445

4.741

LEU449

4.472

PHE489

4.091

LEU493

3.721

LEU496

4.917

LEU506

3.816

LEU509

2.410

VAL510

3.443

ILE512

3.337

Residue

Distance (Å)

THR513

2.491

ASP514

4.577

GLN528

2.764

LEU555

3.294

LEU556

3.852

LYS558

3.693

LEU559

3.877

LEU562

4.141

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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). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

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).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

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
MAPK signaling pathway	hsa04010	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
Aldosterone synthesis and secretion	hsa04925	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Cortisol synthesis and secretion	hsa04927	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	6.53E-06
Closeness centrality	2.37E-01	Radiality	1.42E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	9.13E+01	Topological coefficient	2.93E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

References

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REF 1

Estrogen signaling increases nuclear receptor subfamily 4 group A member 1 expression and energy production in skeletal muscle cells. Endocr J. 2018 Dec 28;65(12):1209-1218.

REF 2

The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nat Chem Biol. 2012 Nov;8(11):897-904.

REF 3

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway. Nat Chem Biol. 2014 Feb;10(2):133-40.

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