Target Information
| Target General Information | Top | |||||
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| Target ID |
T44479
(Former ID: TTDR00293)
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| Target Name |
Gap junction alpha-1 protein (GJA1)
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| Synonyms |
Gap junction 43 kDa heart protein; GJAL; Cx43; Connexin-43; Connexin 43
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| Gene Name |
GJA1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Diabetic foot ulcer [ICD-11: BD54] | |||||
| 2 | Radiation effect [ICD-11: NF00] | |||||
| 3 | Skin postprocedural disorder [ICD-11: EL8Y] | |||||
| Function |
A gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract. May play a role in cell growth inhibition through the regulation of NOV expression and localization. Plays an essential role in gap junction communication in the ventricles. Gap junction protein that acts as a regulator of bladder capacity.
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| BioChemical Class |
Gap junction-forming connexin
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| UniProt ID | ||||||
| Sequence |
MGDWSALGKLLDKVQAYSTAGGKVWLSVLFIFRILLLGTAVESAWGDEQSAFRCNTQQPG
CENVCYDKSFPISHVRFWVLQIIFVSVPTLLYLAHVFYVMRKEEKLNKKEEELKVAQTDG VNVDMHLKQIEIKKFKYGIEEHGKVKMRGGLLRTYIISILFKSIFEVAFLLIQWYIYGFS LSAVYTCKRDPCPHQVDCFLSRPTEKTIFIIFMLVVSLVSLALNIIELFYVFFKGVKDRV KGKSDPYHATSGALSPAKDCGSQKYAYFNGCSSPTAPLSPMSPPGYKLVTGDRNNSSCRN YNKQASEQNWANYSAEQNRMGQAGSTISNSHAQPFDFPDDNQNSKKLAAGHELQPLAIVD QRPSSRASSRASSRPRPDDLEI Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T76B0A | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | Act1 | Drug Info | Phase 3 | Wound healing | [2] | |
| 2 | Granexin gel | Drug Info | Phase 3 | Diabetic foot ulcer | [3], [4] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Act1 | Drug Info | [1] | |||
| 2 | Granexin gel | Drug Info | [8] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | octanol | Drug Info | [9] | |||
| 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: Tetradecane | Ligand Info | |||||
| Structure Description | Structure of connexin43/Cx43/GJA1 gap junction intercellular channel in LMNG/CHS detergents at pH ~8.0 | PDB:7F92 | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [10] |
| PDB Sequence |
GDWSALGKLL
11 DKVQAYSTAG21 GKVWLSVLFI31 FRILLLGTAV41 ESAWGDEQSA51 FRCNTQQPGC 61 ENVCYDKSFP71 ISHVRFWVLQ81 IIFVSVPTLL91 YLAHVFYVMR101 KEEKLNKKRG 149 GLLRTYIISI159 LFKSIFEVAF169 LLIQWYIYGF179 SLSAVYTCKR189 DPCPHQVDCF 199 LSRPTEKTIF209 IIFMLVVSLV219 SLALNIIELF229 YVFFKG
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TRP4
4.075
ALA6
3.800
LEU7
3.730
GLY8
4.005
LEU10
3.798
LEU11
4.338
PHE30
4.722
ILE34
3.893
LEU35
4.656
LEU37
4.438
GLY38
4.431
THR39
3.910
GLU42
3.530
PRO71
3.757
ILE72
4.424
PHE77
3.923
VAL79
4.095
LEU80
4.619
ILE82
3.713
ILE83
3.929
PHE84
4.539
SER86
3.736
VAL87
3.908
PRO88
3.981
LEU90
3.776
LEU91
3.960
TYR92
4.337
HIS95
3.610
PHE97
3.621
TYR98
4.227
THR154
4.118
ILE157
4.401
SER158
3.927
PHE161
4.206
PHE165
3.944
ALA168
4.981
PHE169
3.940
ILE172
4.253
TYR175
4.381
ILE176
4.322
PHE179
4.106
SER180
4.967
THR204
4.040
THR207
4.799
ILE208
4.342
ILE211
4.063
PHE212
3.699
LEU214
4.657
VAL215
4.268
LEU218
3.934
VAL219
3.801
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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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There is no similarity protein (E value < 0.005) for this target
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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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| Gap junction | hsa04540 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Degree | 19 | Degree centrality | 2.04E-03 | Betweenness centrality | 1.70E-03 |
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| Closeness centrality | 2.45E-01 | Radiality | 1.43E+01 | Clustering coefficient | 9.94E-02 |
| Neighborhood connectivity | 3.64E+01 | Topological coefficient | 7.30E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| References | Top | |||||
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| REF 1 | Company report (FirstString Research) | |||||
| REF 2 | ClinicalTrials.gov (NCT01816165) Effects of Acipimox on Insulin Action, Vascular Function, and Muscle Function in Type 1 Diabetes. U.S. National Institutes of Health. | |||||
| REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 4 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 5 | Clinical pipeline report, company report or official report of OcuNexus Therapeutics. | |||||
| REF 6 | ClinicalTrials.gov (NCT04886765) A Phase I/II, Multi-center, Single-Arm, Open-Label Study to Evaluate the Safety and Efficacy of ALMB-0168 in Patients With Osteosarcoma. U.S.National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT05524103) A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ALMB-0166 in Patients With Acute Spinal Cord Injury. U.S.National Institutes of Health. | |||||
| REF 8 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 9 | 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: 728). | |||||
| REF 10 | Conformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM. Nat Commun. 2023 Feb 18;14(1):931. | |||||
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