Target Information
| Target General Information | Top | |||||
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| Target ID |
T88752
(Former ID: TTDI02365)
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| Target Name |
Ras-related C3 botulinum toxin substrate 1 (RAC1)
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| Synonyms |
Cell migration-inducing gene5 protein
Click to Show/Hide
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| Gene Name |
RAC1
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| Target Type |
Literature-reported target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Alzheimer disease [ICD-11: 8A20] | |||||
| Function |
In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states.
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| BioChemical Class |
Small GTPase
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| UniProt ID | ||||||
| EC Number |
EC 3.6.5.2
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| Sequence |
MQAIKCVVVGDGAVGKTCLLISYTTNAFPGEYIPTVFDNYSANVMVDGKPVNLGLWDTAG
QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRAKWYPEVRHHCPNTPIILVGTKLDLR DDKDTIEKLKEKKLTPITYPQGLAMAKEIGAVKYLECSALTQRGLKTVFDEAIRAVLCPP PVKKRKRKCLLL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T46YMA | |||||
| Drugs and Modes of Action | Top | |||||
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| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | EHT-1864 | Drug Info | Terminated | Alzheimer disease | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | EHT-1864 | Drug Info | [1] | |||
| 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: Phosphomethylphosphonic Acid Guanylate Ester | Ligand Info | |||||
| Structure Description | Rac1/PRK1 Complex | PDB:2RMK | ||||
| Method | Solution NMR | Resolution | N.A. | Mutation | Yes | [2] |
| PDB Sequence |
MQAIKCVVVG
10 DGAVGKTCLL20 ISYTTNAFPG30 EYIPTVFDNY40 SANVMVDGKP50 VNLGLWDTAG 60 LEDYDRLRPL70 SYPQTDVFLI80 CFSLVSPASF90 ENVRAKWYPE100 VRHHCPNTPI 110 ILVGTKLDLR120 DDKDTIEKLK130 EKKLTPITYP140 QGLAMAKEIG150 AVKYLECSAL 160 TQRGLKTVFD170 EAIRAVLCPP180 PVKKRKRKCL190 LL
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ALA13
3.901
VAL14
1.674
GLY15
1.728
LYS16
2.109
THR17
1.998
CYS18
1.828
LEU19
3.985
PHE28
2.862
GLY30
3.346
GLU31
4.867
TYR32
4.397
ILE33
4.221
PRO34
3.396
THR35
3.444
ASP57
4.864
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| Ligand Name: 5'-Guanosine-Diphosphate-Monothiophosphate | Ligand Info | |||||
| Structure Description | Activated Rac1 bound to its effector phospholipase C beta 2 | PDB:2FJU | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [3] |
| PDB Sequence |
MQAIKCVVVG
10 DGAVGKTCLL20 ISYTTNAFPG30 EYIPTVFDNY40 SANVMVDGKP50 VNLGLWDTAG 60 QEDYDRLRPL70 SYPQTDVFLI80 CFSLVSPASF90 ENVRAKWYPE100 VRHHCPNTPI 110 ILVGTKLDLR120 DDKDTIEKLK130 EKKLTPITYP140 QGLAMAKEIG150 AVKYLECSAL 160 TQRGLKTVFD170 EAIRAVL
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GLY10
4.720
ASP11
3.784
GLY12
3.417
ALA13
2.955
VAL14
3.452
GLY15
3.075
LYS16
2.742
THR17
2.804
CYS18
2.796
LEU19
4.745
PHE28
3.280
PRO29
4.923
TYR32
3.008
ILE33
4.548
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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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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Leucine-rich repeat kinase 2 (LRRK2) | 24.590 (45/183) | 4.01E-07 | |
| ADP-ribosylation factor-like protein 5A (ARL5A) | 23.030 (38/165) | 4.00E-03 |
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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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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Ras signaling pathway | hsa04014 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Rap1 signaling pathway | hsa04015 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Chemokine signaling pathway | hsa04062 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Sphingolipid signaling pathway | hsa04071 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Phagosome | hsa04145 | Affiliated Target |
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| Class: Cellular Processes => Transport and catabolism | Pathway Hierarchy | ||
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Wnt signaling pathway | hsa04310 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| VEGF signaling pathway | hsa04370 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Osteoclast differentiation | hsa04380 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Focal adhesion | hsa04510 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Adherens junction | hsa04520 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Tight junction | hsa04530 | Affiliated Target |
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| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Toll-like receptor signaling pathway | hsa04620 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Natural killer cell mediated cytotoxicity | hsa04650 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| B cell receptor signaling pathway | hsa04662 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Fc epsilon RI signaling pathway | hsa04664 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Fc gamma R-mediated phagocytosis | hsa04666 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Leukocyte transendothelial migration | hsa04670 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Neurotrophin signaling pathway | hsa04722 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| Regulation of actin cytoskeleton | hsa04810 | Affiliated Target |
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| Class: Cellular Processes => Cell motility | Pathway Hierarchy | ||
| Pancreatic secretion | hsa04972 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 73 | Degree centrality | 7.84E-03 | Betweenness centrality | 5.03E-03 |
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| Closeness centrality | 2.57E-01 | Radiality | 1.44E+01 | Clustering coefficient | 5.94E-02 |
| Neighborhood connectivity | 2.63E+01 | Topological coefficient | 3.14E-02 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases. J Biol Chem. 2007 Dec 7;282(49):35666-78. | |||||
| REF 2 | The Rac1 polybasic region is required for interaction with its effector PRK1. J Biol Chem. 2008 Jan 18;283(3):1492-1500. | |||||
| REF 3 | Crystal structure of Rac1 bound to its effector phospholipase C-beta2. Nat Struct Mol Biol. 2006 Dec;13(12):1135-40. | |||||
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