Target Information

Target General Information

Target ID

T15795

Target Name

TWIK-related acid-sensitive potassium channel 1 (TASK1)

Synonyms

Two pore potassium channel KT3.1; Two pore K(+) channel KT3.1; TWIK-related acid-sensitive K(+) channel 1; Acid-sensitive potassium channel protein TASK-1

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Gene Name

KCNK3

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Obstructive sleep apnoea [ICD-11: 7A41]

Function

pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward.

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UniProt ID

KCNK3_HUMAN

Sequence

MKRQNVRTLALIVCTFTYLLVGAAVFDALESEPELIERQRLELRQQELRARYNLSQGGYE
ELERVVLRLKPHKAGVQWRFAGSFYFAITVITTIGYGHAAPSTDGGKVFCMFYALLGIPL
TLVMFQSLGERINTLVRYLLHRAKKGLGMRRADVSMANMVLIGFFSCISTLCIGAAAFSH
YEHWTFFQAYYYCFITLTTIGFGDYVALQKDQALQTQPQYVAFSFVYILTGLTVIGAFLN
LVVLRFMTMNAEDEKRDAEHRALLTRNGQAGGGGGGGSAHTTDTASSTAAAGGGGFRNVY
AEVLHFQSMCSCLWYKSREKLQYSIPMIIPRDLSTSDTCVEQSHSSPGGGGRYSDTPSRR
CLCSGAPRSAISSVSTGLHSLSTFRGLMKRRSSV

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

BAY 2253651

Drug Info

Phase 2

Obstructive sleep apnea

[2]

BAY-2253651

Drug Info

Phase 2

Obstructive sleep apnea

[1]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 2 Inhibitor drugs

BAY 2253651

Drug Info

[1]

BAY-2253651

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: Cholesterol hemisuccinate

Ligand Info

Structure Description

Crystal structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1) in a closed conformation with a bound inhibitor BAY 1000493

PDB:6RV3

Method

X-ray diffraction

Resolution

2.90 Å

Mutation

[3]

PDB Sequence

MKRQNVRTLA

¹⁰

LIVCTFTYLL

²⁰

VGAAVFDALE

³⁰

SEPELIERQR

⁴⁰

LELRQQELRA

⁵⁰

RYNLSQGGYE

⁶⁰

ELERVVLRLK

⁷⁰

PHKAGVQWRF

⁸⁰

AGSFYFAITV

⁹⁰

ITTIGYGHAA

¹⁰⁰

PSTDGGKVFC

¹¹⁰

MFYALLGIPL

¹²⁰

TLVMFQSLGE

¹³⁰

RINTLVRYLL

¹⁴⁰

HRAKKGLGAD

¹⁵³

VSMANMVLIG

¹⁶³

FFSCISTLCI

¹⁷³

GAAAFSHYEH

¹⁸³

WTFFQAYYYC

¹⁹³

FITLTTIGFG

²⁰³

DYVALQKDQA

²¹³

LQTQPQYVAF

²²³

SFVYILTGLT

²³³

VIGAFLNLVV

²⁴³

LRFMTMNAED

²⁵³

EKRDAENL

Residue

Distance (Å)

ARG3

3.329

VAL6

3.848

ARG7

3.818

ALA10

4.128

LEU11

3.835

CYS14

4.462

ARG79

3.726

PHE80

3.238

ALA81

2.978

GLY82

4.879

PHE84

3.694

LEU214

4.579

Residue

Distance (Å)

GLN215

3.262

PRO218

3.784

VAL221

3.750

ALA222

3.776

PHE225

3.664

VAL226

4.021

THR230

4.862

PHE238

3.710

LEU239

4.966

VAL242

3.738

VAL243

4.101

PHE246

3.567

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Ligand Name: Decyl-beta-D-maltopyranoside

Ligand Info

Structure Description

Crystal structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1) in a closed conformation with a bound inhibitor BAY 1000493

PDB:6RV3

Method

X-ray diffraction

Resolution

2.90 Å

Mutation

[3]

PDB Sequence

MKRQNVRTLA

¹⁰

LIVCTFTYLL

²⁰

VGAAVFDALE

³⁰

SEPELIERQR

⁴⁰

LELRQQELRA

⁵⁰

RYNLSQGGYE

⁶⁰

ELERVVLRLK

⁷⁰

PHKAGVQWRF

⁸⁰

AGSFYFAITV

⁹⁰

ITTIGYGHAA

¹⁰⁰

PSTDGGKVFC

¹¹⁰

MFYALLGIPL

¹²⁰

TLVMFQSLGE

¹³⁰

RINTLVRYLL

¹⁴⁰

HRAKKGLGAD

¹⁵³

VSMANMVLIG

¹⁶³

FFSCISTLCI

¹⁷³

GAAAFSHYEH

¹⁸³

WTFFQAYYYC

¹⁹³

FITLTTIGFG

²⁰³

DYVALQKDQA

²¹³

LQTQPQYVAF

²²³

SFVYILTGLT

²³³

VIGAFLNLVV

²⁴³

LRFMTMNAED

²⁵³

EKRDAENL

Residue

Distance (Å)

LEU128

4.363

ARG131

3.448

ILE132

3.893

Residue

Distance (Å)

THR134

3.850

LEU135

4.355

TYR138

4.399

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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). 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

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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).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Voltage-gated potassium channel Kv10.2 (KCNH5)	PF00027 ; PF00520 ; PF13426 More >>	29.661 (35/118)	8.50E-05
Voltage-gated potassium channel Kv10.1 (KCNH1)	PF00027 ; PF00520 ; PF13426 More >>	29.592 (29/98)	2.36E-04
Voltage-gated potassium channel Kv1.7 (KCNA7)	PF02214 ; PF00520	35.938 (23/64)	5.00E-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
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

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 Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Aldosterone synthesis and secretion

Cortisol synthesis and secretion

Cushing syndrome

References

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REF 1

Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.

REF 2

ClinicalTrials.gov (NCT03603678) Obstructive Sleep Apnea (OSA) Treated With a Potassium Channel Inhibitor (SANDMAN). U.S. National Institutes of Health.

REF 3

A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature. 2020 Jun;582(7812):443-447.

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