Target Information

Target General Information

Target ID

T59875 (Former ID: TTDI03184)

Target Name

Estrogen-related receptor-gamma (ESRRG)

Synonyms

Nuclear receptor subfamily 3 group B member 3; NR3B3; KIAA0832; Estrogen-related receptor gamma; Estrogen receptor-related protein 3; ERRG2; ERR3; ERR gamma-2

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Gene Name

ESRRG

Target Type

Literature-reported target

[1]

Function

Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements. Induces the expression of PERM1 in the skeletal muscle. Orphan receptor that acts as transcription activator in the absence of bound ligand.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

ERR3_HUMAN

Sequence

MDSVELCLPESFSLHYEEELLCRMSNKDRHIDSSCSSFIKTEPSSPASLTDSVNHHSPGG
SSDASGSYSSTMNGHQNGLDSPPLYPSAPILGGSGPVRKLYDDCSSTIVEDPQTKCEYML
NSMPKRLCLVCGDIASGYHYGVASCEACKAFFKRTIQGNIEYSCPATNECEITKRRRKSC
QACRFMKCLKVGMLKEGVRLDRVRGGRQKYKRRIDAENSPYLNPQLVQPAKKPYNKIVSH
LLVAEPEKIYAMPDPTVPDSDIKALTTLCDLADRELVVIIGWAKHIPGFSTLSLADQMSL
LQSAWMEILILGVVYRSLSFEDELVYADDYIMDEDQSKLAGLLDLNNAILQLVKKYKSMK
LEKEEFVTLKAIALANSDSMHIEDVEAVQKLQDVLHEALQDYEAGQHMEDPRRAGKMLMT
LPLLRQTSTKAVQHFYNIKLEGKVPMHKLFLEMLEAKV

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3D Structure

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AlphaFold

HIT2.0 ID

T52NOH

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: Afimoxifene

Ligand Info

Structure Description

Estrogen Related Receptor-gamma ligand binding domain complexed with 4-hydroxy-tamoxifen

PDB:2GPU

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

[3]

PDB Sequence

YNKIVSHLLV

²⁴³

AEPEKIYAMP

²⁵³

DPTVPDSDIK

²⁶³

ALTTLCDLAD

²⁷³

RELVVIIGWA

²⁸³

KHIPGFSTLS

²⁹³

LADQMSLLQS

³⁰³

AWMEILILGV

³¹³

VYRSLSFEDE

³²³

LVYADDYIMD

³³³

EDQSKLAGLL

³⁴³

DLNNAILQLV

³⁵³

KKYKSMKLEK

³⁶³

EEFVTLKAIA

³⁷³

LANSDSMHIE

³⁸³

DVEAVQKLQD

³⁹³

VLHEALQDYE

⁴⁰³

AGQHMEDPRR

⁴¹³

AGKMLMTLPL

⁴²³

LRQTSTKAVQ

⁴³³

HFYNIKLEGK

⁴⁴³

VPMHKLFLEM

⁴⁵³

Residue

Distance (Å)

LEU265

4.075

LEU268

3.613

CYS269

3.843

LEU271

4.178

ALA272

3.386

ASP273

2.656

GLU275

2.604

LEU276

4.436

TRP305

3.575

MET306

3.905

LEU309

3.690

ILE310

4.467

VAL313

4.354

ARG316

3.421

Residue

Distance (Å)

TYR326

3.297

LEU342

3.728

LEU345

4.123

ASN346

4.413

ILE349

3.916

ALA431

3.403

HIS434

3.621

PHE435

3.073

ILE438

4.514

LEU440

3.183

GLU441

3.673

MET446

3.956

LEU449

4.192

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Ligand Name: Bisphenol A

Ligand Info

Structure Description

Crystal structure of human estrogen-related receptor gamma ligand binding domain complex with bisphenol A

PDB:2E2R

Method

X-ray diffraction

Resolution

1.60 Å

Mutation

[4]

PDB Sequence

KPYNKIVSHL

²⁴¹

LVAEPEKIYA

²⁵¹

MPDPTVPDSD

²⁶¹

IKALTTLCDL

²⁷¹

ADRELVVIIG

²⁸¹

WAKHIPGFST

²⁹¹

LSLADQMSLL

³⁰¹

QSAWMEILIL

³¹¹

GVVYRSLSFE

³²¹

DELVYADDYI

³³¹

MDEDQSKLAG

³⁴¹

LLDLNNAILQ

³⁵¹

LVKKYKSMKL

³⁶¹

EKEEFVTLKA

³⁷¹

IALANSDSMH

³⁸¹

IEDVEAVQKL

³⁹¹

QDVLHEALQD

⁴⁰¹

YEAGQHMEDP

⁴¹¹

RRAGKMLMTL

⁴²¹

PLLRQTSTKA

⁴³¹

VQHFYNIKLE

⁴⁴¹

GKVPMHKLFL

⁴⁵¹

EMLEAKVC

Residue

Distance (Å)

LEU268

3.566

CYS269

4.415

LEU271

4.043

ALA272

3.682

GLU275

2.553

TRP305

4.793

MET306

3.588

LEU309

3.546

ILE310

4.386

VAL313

4.135

Residue

Distance (Å)

ARG316

2.980

TYR326

3.065

LEU342

3.979

LEU345

3.409

ASN346

2.770

ILE349

3.590

ALA431

3.988

PHE435

3.636

PHE450

4.358

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Click to View More Binding Site Information of This Target with Different Ligands

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). 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 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).

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

Biological Network Descriptors

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

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	2.03E-01	Radiality	1.35E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	5.20E+01	Topological coefficient	1.00E+00	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

References

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REF 1

Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res. 2003 Nov;1(13):981-91.

REF 2

Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma. J Med Chem. 2005 May 5;48(9):3107-9.

REF 3

X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation. J Biol Chem. 2006 Dec 8;281(49):37773-81.

REF 4

Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma. J Biochem. 2007 Oct;142(4):517-24.

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