Target Information

Target General Information

Target ID

T62184 (Former ID: TTDR01179)

Target Name

GABA transporter GAT-1 (SLC6A1)

Synonyms

Solute carrier family 6 member 1; Sodium- and chloride-dependent GABA transporter 1; GAT1; GAT-1; GABT1; GABATR; GABA transporter 1

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Gene Name

SLC6A1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Epilepsy/seizure [ICD-11: 8A61-8A6Z]

Multiple myeloma [ICD-11: 2A83]

Function

Terminates the action of GABA by its high affinity sodium-dependent reuptake into presynaptic terminals.

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BioChemical Class

Neurotransmitter:sodium symporter

UniProt ID

SC6A1_HUMAN

Sequence

MATNGSKVADGQISTEVSEAPVANDKPKTLVVKVQKKAADLPDRDTWKGRFDFLMSCVGY
AIGLGNVWRFPYLCGKNGGGAFLIPYFLTLIFAGVPLFLLECSLGQYTSIGGLGVWKLAP
MFKGVGLAAAVLSFWLNIYYIVIISWAIYYLYNSFTTTLPWKQCDNPWNTDRCFSNYSMV
NTTNMTSAVVEFWERNMHQMTDGLDKPGQIRWPLAITLAIAWILVYFCIWKGVGWTGKVV
YFSATYPYIMLIILFFRGVTLPGAKEGILFYITPNFRKLSDSEVWLDAATQIFFSYGLGL
GSLIALGSYNSFHNNVYRDSIIVCCINSCTSMFAGFVIFSIVGFMAHVTKRSIADVAASG
PGLAFLAYPEAVTQLPISPLWAILFFSMLLMLGIDSQFCTVEGFITALVDEYPRLLRNRR
ELFIAAVCIISYLIGLSNITQGGIYVFKLFDYYSASGMSLLFLVFFECVSISWFYGVNRF
YDNIQEMVGSRPCIWWKLCWSFFTPIIVAGVFIFSAVQMTPLTMGNYVFPKWGQGVGWLM
ALSSMVLIPGYMAYMFLTLKGSLKQRIQVMVQPSEDIVRPENGPEQPQAGSSTSKEAYI

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Metadoxine

Drug Info

Approved

Multiple myeloma

[2], [3]

Tiagabine

Drug Info

Approved

Epilepsy

[4], [5]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

GSK683699

Drug Info

Phase 2

Inflammatory bowel disease

[6]

CI-966

Drug Info

Phase 1

Convulsion

[7], [8]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 2 Modulator drugs

Metadoxine

Drug Info

[9]

CI-966

Drug Info

[8]

Inhibitor

[+] 12 Inhibitor drugs

Tiagabine

Drug Info

[1]

GSK683699

Drug Info

[10]

(R)-EF-1520

Drug Info

[1]

(R)-nipecotic acid

Drug Info

[10]

(R/S) EF-1500

Drug Info

[1]

(S)-EF-1520

Drug Info

[1]

(S)-Piperidine-3-carboxylic acid

Drug Info

[10]

2,4-Diamino-butyric acid(GABA)

Drug Info

[11]

4-Hydroxy-piperidine-3-carboxylic acid

Drug Info

[12]

LU32-176B

Drug Info

[13]

NIPECOTIC ACID

Drug Info

[14]

SKF89976A

Drug Info

[1]

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: Tiagabine

Ligand Info

Structure Description

Human wildtype GABA reuptake transporter 1 in complex with tiagabine, inward-open conformation

PDB:7SK2

Method

Electron microscopy

Resolution

3.82 Å

Mutation

[15]

PDB Sequence

WKGRFDFLMS

⁵⁶

CVGYAIGLGN

⁶⁶

VWRFPYLCGK

⁷⁶

NGGGAFLIPY

⁸⁶

FLTLIFAGVP

⁹⁶

LFLLECSLGQ

¹⁰⁶

YTSIGGLGVW

¹¹⁶

KLAPMFKGVG

¹²⁶

LAAAVLSFWL

¹³⁶

NIYYIVIISW

¹⁴⁶

AIYYLYNSFT

¹⁵⁶

TTLPWKQCDN

¹⁶⁶

PWNTDRCFSN

¹⁷⁶

YSMVNTTNMT

¹⁸⁶

SAVVEFWERN

¹⁹⁶

MHQMTDGLDK

²⁰⁶

PGQIRWPLAI

²¹⁶

TLAIAWILVY

²²⁶

FCIWKGVGWT

²³⁶

GKVVYFSATY

²⁴⁶

PYIMLIILFF

²⁵⁶

RGVTLPGAKE

²⁶⁶

GILFYITPNF

²⁷⁶

RKLSDSEVWL

²⁸⁶

DAATQIFFSY

²⁹⁶

GLGLGSLIAL

³⁰⁶

GSYNSFHNNV

³¹⁶

YRDSIIVCCI

³²⁶

NSCTSMFAGF

³³⁶

VIFSIVGFMA

³⁴⁶

HVTKRSIADV

³⁵⁶

AASGPGLAFL

³⁶⁶

AYPEAVTQLP

³⁷⁶

ISPLWAILFF

³⁸⁶

SMLLMLGIDS

³⁹⁶

QFCTVEGFIT

⁴⁰⁶

ALVDEYPRLL

⁴¹⁶

RNRRELFIAA

⁴²⁶

VCIISYLIGL

⁴³⁶

SNITQGGIYV

⁴⁴⁶

FKLFDYYSAS

⁴⁵⁶

GMSLLFLVFF

⁴⁶⁶

ECVSISWFYG

⁴⁷⁶

VNRFYDNIQE

⁴⁸⁶

MVGSRPCIWW

⁴⁹⁶

KLCWSFFTPI

⁵⁰⁶

IVAGVFIFSA

⁵¹⁶

VQMTPLTMGN

⁵²⁶

YVFPKWGQGV

⁵³⁶

GWLMALSSMV

⁵⁴⁶

LIPGYMAYMF

⁵⁵⁶

LTLKGSLKQR

⁵⁶⁶

IQVMVQPSED

⁵⁷⁶

Residue

Distance (Å)

GLY59

4.429

TYR60

3.539

ALA61

4.764

ILE62

4.805

GLY63

3.135

LEU64

2.698

GLY65

2.435

ASN66

4.593

PHE98

3.942

LEU136

4.549

TYR140

3.902

PHE294

3.920

Residue

Distance (Å)

SER295

3.506

TYR296

3.253

GLY297

3.621

LEU300

3.743

SER302

3.267

LEU303

3.242

ILE304

4.235

ALA305

3.574

LEU306

3.625

SER396

3.902

CYS399

3.532

THR400

4.145

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). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation

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

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
Synaptic vesicle cycle	hsa04721	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
GABAergic synapse	hsa04727	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

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 Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 1 KEGG Pathways

GABAergic synapse

Reactome

[+] 1 Reactome Pathways

Na+/Cl- dependent neurotransmitter transporters

WikiPathways

[+] 2 WikiPathways

Monoamine Transport

NRF2 pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

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. (Target id: 929).

REF 2

ClinicalTrials.gov (NCT02051842) Effect of Metadoxine on Oxidative Stress in Non-alcoholic Hepatic Steatosis. U.S. National Institutes of Health.

REF 3

Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease. Hum Psychopharmacol. 2011 Dec;26(8):554-9.

REF 4

REF 5

Use of second-generation antiepileptic drugs in the pediatric population. Paediatr Drugs. 2008;10(4):217-54.

REF 6

Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59.

REF 7

REF 8

Tiagabine, SK&F 89976-A, CI-966, and NNC-711 are selective for the cloned GABA transporter GAT-1. Eur J Pharmacol. 1994 Oct 14;269(2):219-24.

REF 9

Company report (Alcobra pharma)

REF 10

Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates: synthesis, in vitro pharmacology, and modeling. J Med Chem. 2004 Nov 4;47(23):5620-9.

REF 11

Glycine antagonists. Synthesis, structure, and biological effects of some bicyclic 5-isoxazolol zwitterions. J Med Chem. 1986 Feb;29(2):224-9.

REF 12

Hydroxy- and amino-substituted piperidinecarboxylic acids as gamma-aminobutyric acid agonists and uptake inhibitors. J Med Chem. 1982 Oct;25(10):1157-62.

REF 13

First demonstration of a functional role for central nervous system betaine/{gamma}-aminobutyric acid transporter (mGAT2) based on synergistic anti... J Pharmacol Exp Ther. 2005 Feb;312(2):866-74.

REF 14

Epimeric cis-decahydroquinoline-5-carboxylic acids: effects on gamma-aminobutyric acid uptake and receptor binding in vitro. J Med Chem. 1981 Jul;24(7):788-94.

REF 15

Structural basis of GABA reuptake inhibition. Nature. 2022 Jun;606(7915):820-826.

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