Target Information

Target General Information

Target ID

T11615 (Former ID: TTDR01200)

Target Name

Cystine/glutamate transporter (SLC7A11)

Synonyms

XCT; X(c)-cystine transporter; X(c)- plasma membrane cystine transporter; Solute carrier family 7 member 11; Calcium channel blocker resistance protein CCBR1; Amino acid transport system xc-; Amino acid transport system XCT

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Gene Name

SLC7A11

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Body-focused behaviour disorder [ICD-11: 6B25]

Function

Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for anionic form of cystine and glutamate.

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BioChemical Class

Amino acid-polyamine-organocation

UniProt ID

XCT_HUMAN

Sequence

MVRKPVVSTISKGGYLQGNVNGRLPSLGNKEPPGQEKVQLKRKVTLLRGVSIIIGTIIGA
GIFISPKGVLQNTGSVGMSLTIWTVCGVLSLFGALSYAELGTTIKKSGGHYTYILEVFGP
LPAFVRVWVELLIIRPAATAVISLAFGRYILEPFFIQCEIPELAIKLITAVGITVVMVLN
SMSVSWSARIQIFLTFCKLTAILIIIVPGVMQLIKGQTQNFKDAFSGRDSSITRLPLAFY
YGMYAYAGWFYLNFVTEEVENPEKTIPLAICISMAIVTIGYVLTNVAYFTTINAEELLLS
NAVAVTFSERLLGNFSLAVPIFVALSCFGSMNGGVFAVSRLFYVASREGHLPEILSMIHV
RKHTPLPAVIVLHPLTMIMLFSGDLDSLLNFLSFARWLFIGLAVAGLIYLRYKCPDMHRP
FKVPLFIPALFSFTCLFMVALSLYSDPFSTGIGFVITLTGVPAYYLFIIWDKKPRWFRIM
SEKITRTLQIILEVVPEEDKL

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3D Structure

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AlphaFold

HIT2.0 ID

T43WIP

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: 2-[(1S)-1-[4-[2-(4-chloranylphenoxy)ethanoyl]piperazin-1-yl]ethyl]-3-(2-ethoxyphenyl)quinazolin-4-one

Ligand Info

Structure Description

Overall structure of Erastin-bound xCT-4F2hc complex

PDB:7EPZ

Method

Electron microscopy

Resolution

3.40 Å

Mutation

[3]

PDB Sequence

TLLRGVSIII

⁵⁴

GTIIGAGIFI

⁶⁴

SPKGVLQNTG

⁷⁴

SVGMSLTIWT

⁸⁴

VCGVLSLFGA

⁹⁴

LSYAELGTTI

¹⁰⁴

KKSGGHYTYI

¹¹⁴

LEVFGPLPAF

¹²⁴

VRVWVELLII

¹³⁴

RPAATAVISL

¹⁴⁴

AFGRYILEPF

¹⁵⁴

FIQCEIPELA

¹⁶⁴

IKLITAVGIT

¹⁷⁴

VVMVLNSMSV

¹⁸⁴

SWSARIQIFL

¹⁹⁴

TFCKLTAILI

²⁰⁴

IIVPGVMQLI

²¹⁴

KGQTQNFKDA

²²⁴

FSGRDSSITR

²³⁴

LPLAFYYGMY

²⁴⁴

AYAGWFYLNF

²⁵⁴

VTEEVENPEK

²⁶⁴

TIPLAICISM

²⁷⁴

AIVTIGYVLT

²⁸⁴

NVAYFTTINA

²⁹⁴

EELLLSNAVA

³⁰⁴

VTFSERLLGN

³¹⁴

FSLAVPIFVA

³²⁴

LSCFGSMNGG

³³⁴

VFAVSRLFYV

³⁴⁴

ASREGHLPEI

³⁵⁴

LSMIHVRKHT

³⁶⁴

PLPAVIVLHP

³⁷⁴

LTMIMLFSGD

³⁸⁴

LDSLLNFLSF

³⁹⁴

ARWLFIGLAV

⁴⁰⁴

AGLIYLRYKC

⁴¹⁴

PDMHRPFKVP

⁴²⁴

LFIPALFSFT

⁴³⁴

CLFMVALSLY

⁴⁴⁴

SDPFSTGIGF

⁴⁵⁴

VITLTGVPAY

⁴⁶⁴

YLFIIWDKKP

⁴⁷⁴

RWFRIMSEKI

⁴⁸⁴

TRTLQIILEV

⁴⁹⁴

VPE

Residue

Distance (Å)

GLY49

4.663

ILE52

2.703

THR56

4.225

VAL184

4.692

SER187

3.792

ALA188

4.668

GLN191

3.272

TYR251

3.628

Residue

Distance (Å)

LEU252

2.881

ASN253

4.451

PHE254

2.977

VAL259

4.109

ILE266

3.448

ASN332

4.392

PHE336

3.617

ARG340

4.367

Ligand Name: Distearoyl phosphatidic acid

Ligand Info

Structure Description

Overall structure of Erastin-bound xCT-4F2hc complex

PDB:7EPZ

Method

Electron microscopy

Resolution

3.40 Å

Mutation

[3]

PDB Sequence

TLLRGVSIII

⁵⁴

GTIIGAGIFI

⁶⁴

SPKGVLQNTG

⁷⁴

SVGMSLTIWT

⁸⁴

VCGVLSLFGA

⁹⁴

LSYAELGTTI

¹⁰⁴

KKSGGHYTYI

¹¹⁴

LEVFGPLPAF

¹²⁴

VRVWVELLII

¹³⁴

RPAATAVISL

¹⁴⁴

AFGRYILEPF

¹⁵⁴

FIQCEIPELA

¹⁶⁴

IKLITAVGIT

¹⁷⁴

VVMVLNSMSV

¹⁸⁴

SWSARIQIFL

¹⁹⁴

TFCKLTAILI

²⁰⁴

IIVPGVMQLI

²¹⁴

KGQTQNFKDA

²²⁴

FSGRDSSITR

²³⁴

LPLAFYYGMY

²⁴⁴

AYAGWFYLNF

²⁵⁴

VTEEVENPEK

²⁶⁴

TIPLAICISM

²⁷⁴

AIVTIGYVLT

²⁸⁴

NVAYFTTINA

²⁹⁴

EELLLSNAVA

³⁰⁴

VTFSERLLGN

³¹⁴

FSLAVPIFVA

³²⁴

LSCFGSMNGG

³³⁴

VFAVSRLFYV

³⁴⁴

ASREGHLPEI

³⁵⁴

LSMIHVRKHT

³⁶⁴

PLPAVIVLHP

³⁷⁴

LTMIMLFSGD

³⁸⁴

LDSLLNFLSF

³⁹⁴

ARWLFIGLAV

⁴⁰⁴

AGLIYLRYKC

⁴¹⁴

PDMHRPFKVP

⁴²⁴

LFIPALFSFT

⁴³⁴

CLFMVALSLY

⁴⁴⁴

SDPFSTGIGF

⁴⁵⁴

VITLTGVPAY

⁴⁶⁴

YLFIIWDKKP

⁴⁷⁴

RWFRIMSEKI

⁴⁸⁴

TRTLQIILEV

⁴⁹⁴

VPE

Residue

Distance (Å)

TRP128

4.122

LEU132

3.784

VAL178

4.156

SER181

4.306

MET182

3.979

GLY349

4.396

HIS350

4.160

LEU351

3.181

PRO352

3.295

GLU353

3.811

HIS359

4.449

ARG361

3.675

LEU366

3.792

VAL369

4.659

ILE370

3.779

Residue

Distance (Å)

HIS373

3.467

PRO374

4.261

LEU375

4.387

ILE378

4.345

MET379

3.823

PHE391

4.779

ILE456

4.293

PHE467

4.026

LYS472

4.171

PHE477

3.907

SER481

4.543

LEU488

4.933

ILE491

4.258

LEU492

4.126

GLU493

4.523

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

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	Pathway Map
Ferroptosis	hsa04216	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	1.76E-04
Closeness centrality	2.00E-01	Radiality	1.35E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	2.80E+01	Topological coefficient	5.09E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

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

References

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REF 1

Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia. 2001 Oct;15(10):1633-40.

REF 2

ClinicalTrials.gov (NCT03797521) A Study in Patients With Trichotillomania (TTM). U.S. National Institutes of Health.

REF 3

The structure of erastin-bound xCT-4F2hc complex?reveals molecular mechanisms underlying erastin-induced ferroptosis. Cell Res. 2022 Jul;32(7):687-690.

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