Target Information

Target General Information

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Target ID

T60077 (Former ID: TTDI03515)

Target Name

Retinoic acid receptor RXR-beta (RXRB)

Synonyms

Retinoid X receptor beta; Nuclear receptor subfamily 2 group B member 2; NR2B2

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Gene Name

RXRB

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Kaposi sarcoma [ICD-11: 2B57]

Function

Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE). Receptor for retinoic acid.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

RXRB_HUMAN

Sequence

MSWAARPPFLPQRHAAGQCGPVGVRKEMHCGVASRWRRRRPWLDPAAAAAAAVAGGEQQT
PEPEPGEAGRDGMGDSGRDSRSPDSSSPNPLPQGVPPPSPPGPPLPPSTAPSLGGSGAPP
PPPMPPPPLGSPFPVISSSMGSPGLPPPAPPGFSGPVSSPQINSTVSLPGGGSGPPEDVK
PPVLGVRGLHCPPPPGGPGAGKRLCAICGDRSSGKHYGVYSCEGCKGFFKRTIRKDLTYS
CRDNKDCTVDKRQRNRCQYCRYQKCLATGMKREAVQEERQRGKDKDGDGEGAGGAPEEMP
VDRILEAELAVEQKSDQGVEGPGGTGGSGSSPNDPVTNICQAADKQLFTLVEWAKRIPHF
SSLPLDDQVILLRAGWNELLIASFSHRSIDVRDGILLATGLHVHRNSAHSAGVGAIFDRV
LTELVSKMRDMRMDKTELGCLRAIILFNPDAKGLSNPSEVEVLREKVYASLETYCKQKYP
EQQGRFAKLLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLEAPHQLA

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3D Structure

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AlphaFold

HIT2.0 ID

T01P7T

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Alitretinoin

Drug Info

Approved

Kaposi sarcoma

[2], [3]

Mode of Action

[+] 3 Modes of Action

Agonist

[+] 1 Agonist drugs

Alitretinoin

Drug Info

[1]

Inhibitor

[+] 1 Inhibitor drugs

AGN-34

Drug Info

[4]

Antagonist

[+] 1 Antagonist drugs

LG100754

Drug Info

[5]

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: Methoprene acid

Ligand Info

Structure Description

Crystal structure of the LXRalfa-RXRbeta LBD heterodimer

PDB:1UHL

Method

X-ray diffraction

Resolution

2.90 Å

Mutation

[6]

PDB Sequence

EMPVDRILEA

³⁰⁷

ELAVEQSPND

³³⁴

PVTNICQAAD

³⁴⁴

KQLFTLVEWA

³⁵⁴

KRIPHFSSLP

³⁶⁴

LDDQVILLRA

³⁷⁴

GWNELLIASF

³⁸⁴

SHRSIDVRDG

³⁹⁴

ILLATGLHVH

⁴⁰⁴

RNSAHSAGVG

⁴¹⁴

AIFDRVLTEL

⁴²⁴

VSKMRDMRMD

⁴³⁴

KTELGCLRAI

⁴⁴⁴

ILFNPDAKGL

⁴⁵⁴

SNPSEVEVLR

⁴⁶⁴

EKVYASLETY

⁴⁷⁴

CKQKYPEQQG

⁴⁸⁴

RFAKLLLRLP

⁴⁹⁴

ALRSIGLKCL

⁵⁰⁴

EHLFFFKLIG

⁵¹⁴

DTPIDTFLME

⁵²⁴

MLEA

Residue

Distance (Å)

ILE339

3.512

ALA342

3.146

ALA343

3.224

GLN346

3.770

TRP376

4.273

ASN377

3.759

LEU380

3.522

ILE381

3.721

PHE384

3.606

ARG387

2.693

Residue

Distance (Å)

LEU397

3.990

ALA398

3.307

VAL413

3.450

ILE416

4.010

PHE417

4.487

CYS503

3.354

HIS506

3.930

LEU507

3.662

PHE510

4.849

Ligand Name: LG100268

Ligand Info

Structure Description

The structure of the human retinoid-X-receptor beta ligand binding domain in complex with the specific synthetic agonist LG100268

PDB:1H9U

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

[7]

PDB Sequence

MPVDRILEAE

³⁰⁸

LAVPVTNICQ

³⁴¹

AADKQLFTLV

³⁵¹

EWAKRIPHFS

³⁶¹

SLPLDDQVIL

³⁷¹

LRAGWNELLI

³⁸¹

ASFSHRSIDV

³⁹¹

RDGILLATGL

⁴⁰¹

HVHRNSAHSA

⁴¹¹

GVGAIFDRVL

⁴²¹

TELVSKMRDM

⁴³¹

RMDKTELGCL

⁴⁴¹

RAIILFNPDA

⁴⁵¹

KGLSNPSEVE

⁴⁶¹

VLREKVYASL

⁴⁷¹

ETYCKQKYPE

⁴⁸¹

QQGRFAKLLL

⁴⁹¹

RLPALRSIGL

⁵⁰¹

KCLEHLFFFK

⁵¹¹

LIGDTPIDTF

⁵²¹

Residue

Distance (Å)

VAL336

4.193

ILE339

3.503

CYS340

4.234

ALA342

2.849

ALA343

3.514

GLN346

3.604

TRP376

3.669

ASN377

3.914

LEU380

3.230

ILE381

3.404

PHE384

3.384

ARG387

2.940

LEU396

4.788

Residue

Distance (Å)

LEU397

3.171

ALA398

2.646

THR399

4.573

VAL413

4.092

ILE416

3.680

PHE417

4.448

VAL420

3.973

ILE499

4.644

CYS503

3.470

HIS506

3.645

LEU507

4.112

PHE510

4.920

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). 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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Intersectin-2 (ITSN2)	PF00168 ; PF12763 ; PF16652 ; PF00621 ; PF00018 ; PF07653 ; PF14604 More >>	32.479 (38/117)	4.00E-03


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
PPAR signaling pathway	hsa03320	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Th17 cell differentiation	hsa04659	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Thyroid hormone signaling pathway	hsa04919	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Adipocytokine signaling pathway	hsa04920	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Parathyroid hormone synthesis, secretion and action	hsa04928	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	9	Degree centrality	9.67E-04	Betweenness centrality	2.17E-05
Closeness centrality	2.09E-01	Radiality	1.37E+01	Clustering coefficient	8.33E-02
Neighborhood connectivity	1.53E+01	Topological coefficient	1.85E-01	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

Co-Targets

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Co-Targets

Co-Targets Info

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-interacting Proteins

Target-interacting Proteins Info

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2645).

REF 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

Farnesoid X receptor: from structure to potential clinical applications. J Med Chem. 2005 Aug 25;48(17):5383-403.

REF 5

Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature. 1996 Oct 3;383(6599):450-3.

REF 6

Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation. EMBO J. 2003 Sep 15;22(18):4625-33.

REF 7

The structural basis for the specificity of retinoid-X receptor-selective agonists: new insights into the role of helix H12. J Biol Chem. 2002 Mar 29;277(13):11385-91.

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