Target Information
| Target General Information | Top | |||||
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| Target ID |
T74483
(Former ID: TTDR00544)
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| Target Name |
Voltage-gated potassium channel Kv7.2 (KCNQ2)
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| Synonyms |
Voltage-gated potassium channel subunit Kv7.2; Neuroblastoma-specific potassium channel alpha subunit KvLQT2; Neuroblastoma-specific potassium channel KQT-like 2; KQT-like 2; KCNQ2; K+ channel KCNQ2
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| Gene Name |
KCNQ2
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Pain [ICD-11: MG30-MG3Z] | |||||
| Function |
Probably importantin the regulation of neuronal excitability. Associates with kcnq3 to form a potassium channel with essentially identical properties to the channel underlying the native m-current.
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| BioChemical Class |
Voltage-gated ion channel
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| UniProt ID | ||||||
| Sequence |
MVQKSRNGGVYPGPSGEKKLKVGFVGLDPGAPDSTRDGALLIAGSEAPKRGSILSKPRAG
GAGAGKPPKRNAFYRKLQNFLYNVLERPRGWAFIYHAYVFLLVFSCLVLSVFSTIKEYEK SSEGALYILEIVTIVVFGVEYFVRIWAAGCCCRYRGWRGRLKFARKPFCVIDIMVLIASI AVLAAGSQGNVFATSALRSLRFLQILRMIRMDRRGGTWKLLGSVVYAHSKELVTAWYIGF LCLILASFLVYLAEKGENDHFDTYADALWWGLITLTTIGYGDKYPQTWNGRLLAATFTLI GVSFFALPAGILGSGFALKVQEQHRQKHFEKRRNPAAGLIQSAWRFYATNLSRTDLHSTW QYYERTVTVPMYSSQTQTYGASRLIPPLNQLELLRNLKSKSGLAFRKDPPPEPSPSKGSP CRGPLCGCCPGRSSQKVSLKDRVFSSPRGVAAKGKGSPQAQTVRRSPSADQSLEDSPSKV PKSWSFGDRSRARQAFRIKGAASRQNSEEASLPGEDIVDDKSCPCEFVTEDLTPGLKVSI RAVCVMRFLVSKRKFKESLRPYDVMDVIEQYSAGHLDMLSRIKSLQSRVDQIVGRGPAIT DKDRTKGPAEAELPEDPSMMGRLGKVEKQVLSMEKKLDFLVNIYMQRMGIPPTETEAYFG AKEPEPAPPYHSPEDSREHVDRHGCIVKIVRSSSSTGQKNFSAPPAAPPVQCPPSTSWQP QSHPRQGHGTSPVGDHGSLVRIPPPPAHERSLSAYGGGNRASMEFLRQEDTPGCRPPEGN LRDSDTSISIPSVDHEELERSFSGFSISQSKENLDALNSCYAAVAPCAKVRPYIAEGESD TDSDLCTPCGPPPRSATGEGPFGDVGWAGPRK Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
| 1 | ICA-69673 | Drug Info | Preclinical | Pain | [2] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | ICA-69673 | Drug Info | [1] | |||
| Activator | [+] 6 Activator drugs | + | ||||
| 1 | (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide | Drug Info | [3] | |||
| 2 | ICA-27243 | Drug Info | [4] | |||
| 3 | PIP2 | Drug Info | [6] | |||
| 4 | QO-58 | Drug Info | [7] | |||
| 5 | zinc pyrithione | Drug Info | [9] | |||
| 6 | ztz240 | Drug Info | [10] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | PD-32577 | Drug Info | [5] | |||
| Blocker (channel blocker) | [+] 2 Blocker (channel blocker) drugs | + | ||||
| 1 | XE991 | Drug Info | [8] | |||
| 2 | [14C]TEA | Drug Info | [11] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Retigabine | Ligand Info | |||||
| Structure Description | human KCNQ2 in complex with retigabine | PDB:7CR2 | ||||
| Method | Electron microscopy | Resolution | 3.20 Å | Mutation | No | [12] |
| PDB Sequence |
RNAFYRKLQN
79 FLYNVLERPR89 GWAFIYHAYV99 FLLVFSCLVL109 SVFSTIKEYE119 KSSEGALYIL 129 EIVTIVVFGV139 EYFVRIWAAG149 CCCRYRGWRG159 RLKFARKPFC169 VIDIMVLIAS 179 IAVLASALRS199 LRFLQILRMI209 RMDRRGGTWK219 LLGSVVYAHS229 KELVTAWYIG 239 FLCLILASFL249 VYLAEKGEND259 HFDTYADALW269 WGLITLTTIG279 YGDKYPQTWN 289 GRLLAATFTL299 IGVSFFALPA309 GILGSGFALK319 VQEQHRQKHF329 E |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: ZTZ240 | Ligand Info | |||||
| Structure Description | human KCNQ2 in complex with ztz240 | PDB:7CR1 | ||||
| Method | Electron microscopy | Resolution | 3.40 Å | Mutation | No | [12] |
| PDB Sequence |
RNAFYRKLQN
79 FLYNVLERPR89 GWAFIYHAYV99 FLLVFSCLVL109 SVFSTIKEYE119 KSSEGALYIL 129 EIVTIVVFGV139 EYFVRIWAAG149 CCCRYRGWRG159 RLKFARKPFC169 VIDIMVLIAS 179 IAVLASALRS199 LRFLQILRMI209 RMDRRGGTWK219 LLGSVVYAHS229 KELVTAWYIG 239 FLCLILASFL249 VYLAEKGEND259 HFDTYADALW269 WGLITLTTIG279 YGDKYPQTWN 289 GRLLAATFTL299 IGVSFFALPA309 GILGSGFALK319 VQEQHRQKHF329 |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cholinergic synapse | hsa04725 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.52E-01 | Radiality | 1.20E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 9.00E+00 | Topological coefficient | 1.00E+00 | Eccentricity | 14 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Cholinergic synapse | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Muscarinic acetylcholine receptor 1 and 3 signaling pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Voltage gated Potassium channels | |||||
| 2 | Interaction between L1 and Ankyrins | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Potassium Channels | |||||
| 2 | L1CAM interactions | |||||
| References | Top | |||||
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| REF 1 | Voltage-gated Potassium Channels as Therapeutic Drug Targets | |||||
| REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011004) | |||||
| REF 3 | The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology. 2006 Nov;51(6):1068-77. | |||||
| REF 4 | The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site. Neurosci Lett. 2009 Nov 13;465(2):138-42. | |||||
| REF 5 | Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52. | |||||
| REF 6 | Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci. 2005 Oct 26;25(43):9825-35. | |||||
| REF 7 | Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58. Br J Pharmacol. 2013 Feb;168(4):1030-42. | |||||
| REF 8 | KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science. 1998 Dec 4;282(5395):1890-3. | |||||
| REF 9 | Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants. Nat Chem Biol. 2007 May;3(5):287-96. | |||||
| REF 10 | Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions. J Biol Chem. 2010 Sep 3;285(36):28322-32. | |||||
| REF 11 | Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol. 2000 Sep;58(3):591-600. | |||||
| REF 12 | Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res. 2021 Jan;31(1):52-61. | |||||
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