Target Information

Target General Information

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Target ID

T55916 (Former ID: TTDS00149)

Target Name

Voltage-gated potassium channel Kv7.4 (KCNQ4)

Synonyms

Voltage-gated potassium channel subunit Kv7.4; Potassium channel alpha subunit KvLQT4; KQT-like 4; KCNQ4

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Gene Name

KCNQ4

Target Type

Literature-reported target

[1]

Function

Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1muscarinic receptors.

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BioChemical Class

Voltage-gated ion channel

UniProt ID

KCNQ4_HUMAN

Sequence

MAEAPPRRLGLGPPPGDAPRAELVALTAVQSEQGEAGGGGSPRRLGLLGSPLPPGAPLPG
PGSGSGSACGQRSSAAHKRYRRLQNWVYNVLERPRGWAFVYHVFIFLLVFSCLVLSVLST
IQEHQELANECLLILEFVMIVVFGLEYIVRVWSAGCCCRYRGWQGRFRFARKPFCVIDFI
VFVASVAVIAAGTQGNIFATSALRSMRFLQILRMVRMDRRGGTWKLLGSVVYAHSKELIT
AWYIGFLVLIFASFLVYLAEKDANSDFSSYADSLWWGTITLTTIGYGDKTPHTWLGRVLA
AGFALLGISFFALPAGILGSGFALKVQEQHRQKHFEKRRMPAANLIQAAWRLYSTDMSRA
YLTATWYYYDSILPSFRELALLFEHVQRARNGGLRPLEVRRAPVPDGAPSRYPPVATCHR
PGSTSFCPGESSRMGIKDRIRMGSSQRRTGPSKQHLAPPTMPTSPSSEQVGEATSPTKVQ
KSWSFNDRTRFRASLRLKPRTSAEDAPSEEVAEEKSYQCELTVDDIMPAVKTVIRSIRIL
KFLVAKRKFKETLRPYDVKDVIEQYSAGHLDMLGRIKSLQTRVDQIVGRGPGDRKAREKG
DKGPSDAEVVDEISMMGRVVKVEKQVQSIEHKLDLLLGFYSRCLRSGTSASLGAVQVPLF
DPDITSDYHSPVDHEDISVSAQTLSISRSVSTNMD

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3D Structure

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PDB

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: (1S,2S,4R)-N-(2,4,6-trimethylphenyl)bicyclo[2.2.1]heptane-2-carboxamid

Ligand Info

Structure Description

Structure of human KCNQ4-ML213 complex with PIP2

PDB:7VNP

Method

Electron microscopy

Resolution

2.79 Å

Mutation

[8]

PDB Sequence

SAAHKRYRRL

⁸³

QNWVYNVLER

⁹³

PRGWAFVYHV

¹⁰³

FIFLLVFSCL

¹¹³

VLSVLSTIQE

¹²³

HQELANECLL

¹³³

ILEFVMIVVF

¹⁴³

GLEYIVRVWS

¹⁵³

AGCCCRYRGW

¹⁶³

QGRFRFARKP

¹⁷³

FCVIDFIVFV

¹⁸³

ASVAVIAATS

²⁰¹

ALRSMRFLQI

²¹¹

LRMVRMDRRG

²²¹

GTWKLLGSVV

²³¹

YAHSKELITA

²⁴¹

WYIGFLVLIF

²⁵¹

ASFLVYLAEK

²⁶¹

DANSDFSSYA

²⁷¹

DSLWWGTITL

²⁸¹

TTIGYGDKTP

²⁹¹

HTWLGRVLAA

³⁰¹

GFALLGISFF

³¹¹

ALPAGILGSG

³²¹

FALKVQEQHR

³³¹

QKHFEKRRMP

³⁴¹

AANLIQAAWR

³⁵¹

LYSTDPAVKT

⁵³²

VIRSIRILKF

⁵⁴²

LVAKRKFKET

⁵⁵²

LRPYDVKDVI

⁵⁶²

EQYSAGHLDM

⁵⁷²

LGRIKSLQTR

⁵⁸²

Residue

Distance (Å)

LEU227

4.592

VAL231

3.630

LEU238

4.588

ALA241

3.600

TRP242

2.778

TYR243

4.809

GLY245

4.123

PHE246

3.892

Residue

Distance (Å)

LEU305

3.250

LEU306

2.280

SER309

2.323

PHE310

3.309

PHE311

3.074

PRO314

2.664

LEU318

3.241

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate

Ligand Info

Structure Description

Structure of human KCNQ4-ML213 complex with PIP2

PDB:7VNP

Method

Electron microscopy

Resolution

2.79 Å

Mutation

[8]

PDB Sequence

SAAHKRYRRL

⁸³

QNWVYNVLER

⁹³

PRGWAFVYHV

¹⁰³

FIFLLVFSCL

¹¹³

VLSVLSTIQE

¹²³

HQELANECLL

¹³³

ILEFVMIVVF

¹⁴³

GLEYIVRVWS

¹⁵³

AGCCCRYRGW

¹⁶³

QGRFRFARKP

¹⁷³

FCVIDFIVFV

¹⁸³

ASVAVIAATS

²⁰¹

ALRSMRFLQI

²¹¹

LRMVRMDRRG

²²¹

GTWKLLGSVV

²³¹

YAHSKELITA

²⁴¹

WYIGFLVLIF

²⁵¹

ASFLVYLAEK

²⁶¹

DANSDFSSYA

²⁷¹

DSLWWGTITL

²⁸¹

TTIGYGDKTP

²⁹¹

HTWLGRVLAA

³⁰¹

GFALLGISFF

³¹¹

ALPAGILGSG

³²¹

FALKVQEQHR

³³¹

QKHFEKRRMP

³⁴¹

AANLIQAAWR

³⁵¹

LYSTDPAVKT

⁵³²

VIRSIRILKF

⁵⁴²

LVAKRKFKET

⁵⁵²

LRPYDVKDVI

⁵⁶²

EQYSAGHLDM

⁵⁷²

LGRIKSLQTR

⁵⁸²

Residue

Distance (Å)

ARG93

3.241

ARG95

2.771

PHE99

3.315

PHE106

2.826

ARG159

3.500

LYS172

2.936

PRO173

4.614

PHE174

4.457

ILE177

3.569

LEU212

3.183

VAL215

3.636

ARG216

4.759

Residue

Distance (Å)

MET217

3.619

ASP218

2.786

ARG219

2.502

ARG220

2.662

GLY221

3.380

GLY222

4.041

THR223

3.389

TRP224

3.000

LYS225

2.576

HIS330

3.335

LYS333

3.086

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 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 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 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 Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Calcium-activated potassium channel KCa2.1 (KCNN1)	PF02888 ; PF07885 ; PF03530 More >>	27.679 (31/112)	6.83E-07
Calcium-activated potassium channel KCa3.1 (KCNN4)	PF02888 ; PF07885 ; PF03530 More >>	26.168 (28/107)	7.16E-07
Calcium-activated potassium channel KCa2.3 (KCNN3)	PF02888 ; PF07885 ; PF03530 More >>	27.679 (31/112)	1.06E-06
Calcium-activated potassium channel KCa2.2 (KCNN2)	PF02888 ; PF07885 ; PF03530 More >>	27.184 (28/103)	2.12E-05

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Cholinergic synapse	hsa04725	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

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Cholinergic synapse

Reactome

[+] 1 Reactome Pathways

Voltage gated Potassium channels

WikiPathways

[+] 1 WikiPathways

Potassium Channels

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Identification of novel KCNQ4 openers by a high-throughput fluorescence-based thallium flux assay. Anal Biochem. 2011 Nov 1;418(1):66-72.

REF 2

The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology. 2006 Nov;51(6):1068-77.

REF 3

Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener. ACS Chem Neurosci. 2011 Oct 19;2(10):572-577.

REF 4

Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci. 2005 Oct 26;25(43):9825-35.

REF 5

KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol Cell Physiol. 2001 Apr;280(4):C859-66.

REF 6

Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants. Nat Chem Biol. 2007 May;3(5):287-96.

REF 7

Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. J Biol Chem. 2008 Nov 7;283(45):30668-76.

REF 8

Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel. Neuron. 2022 Jan 19;110(2):237-247.e4.

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