Target Information

Target General Information

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Target ID

T06525 (Former ID: TTDI01491)

Target Name

Rac family small GTPase 3 (RAC3)

Synonyms

p21-Rac3; Ras-related C3 botulinum toxin substrate 3

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Gene Name

RAC3

Target Type

Literature-reported target

[1]

Function

Plasma membrane-associated small GTPase which cycles between an active GTP-bound and inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses, such as cell spreading and the formation of actin-based protusions including lamellipodia and membrane ruffles. Promotes cell adhesion and spreading on fibrinogen in a CIB1 and alpha-IIb/beta3 integrin-mediated manner.

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UniProt ID

RAC3_HUMAN

Sequence

MQAIKCVVVGDGAVGKTCLLISYTTNAFPGEYIPTVFDNYSANVMVDGKPVNLGLWDTAG
QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRAKWYPEVRHHCPHTPILLVGTKLDLR
DDKDTIERLRDKKLAPITYPQGLAMAREIGSVKYLECSALTQRGLKTVFDEAIRAVLCPP
PVKKPGKKCTVF

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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: Guanosine-5'-Diphosphate

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF THE HUMAN RAC3 IN COMPLEX WITH GDP

PDB:2C2H

Method

X-ray diffraction

Resolution

1.85 Å

Mutation

[2]

PDB Sequence

AIKCVVVGDG

¹²

AVGKTCLLIS

²²

YTTNAFPGDN

³⁹

YSANVMVDGK

⁴⁹

PVNLGLWDTA

⁵⁹

GQEDYDRLRP

⁶⁹

LSYPQTDVFL

⁷⁹

ICFSLVSPAS

⁸⁹

FENVRAKWYP

⁹⁹

EVRHHCPHTP

¹⁰⁹

ILLVGTKLDL

¹¹⁹

RDDKDTIERL

¹²⁹

RDKKLAPITY

¹³⁹

PQGLAMAREI

¹⁴⁹

GSVKYLECSA

¹⁵⁹

LTQRGLKTVF

¹⁶⁹

DEAIRAVL

Residue

Distance (Å)

ASP11

3.860

GLY12

3.897

ALA13

2.811

VAL14

3.330

GLY15

3.021

LYS16

2.700

THR17

2.919

CYS18

2.768

LEU19

4.880

PHE28

3.427

ASP57

4.796

PRO99

3.039

GLU100

3.452

HIS103

2.948

HIS104

2.871

Residue

Distance (Å)

PRO106

3.449

HIS107

2.912

LYS116

3.134

LEU117

3.759

ASP118

2.717

LEU119

3.491

ARG120

3.263

TYR139

3.337

PRO140

4.307

GLU156

2.654

SER158

3.483

ALA159

2.935

LEU160

3.157

ARG163

3.122

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Ligand Name: Phosphomethylphosphonic Acid Guanylate Ester

Ligand Info

Structure Description

Crystal structure of human RAC3 in complex with CRIB domain of human p21-activated kinase 1 (PAK1)

PDB:2QME

Method

X-ray diffraction

Resolution

1.75 Å

Mutation

[3]

PDB Sequence

MQAIKCVVVG

¹⁰

DGAVGKTCLL

²⁰

ISYTTNAFPG

³⁰

EYIPTVFDNY

⁴⁰

SANVMVDGKP

⁵⁰

VNLGLWDTAG

⁶⁰

QEDYDRLRPL

⁷⁰

SYPQTDVFLI

⁸⁰

CFSLVSPASF

⁹⁰

ENVRAKWYPE

¹⁰⁰

VRHHCPHTPI

¹¹⁰

LLVGTKLDLR

¹²⁰

DDKDTIERLR

¹³⁰

DKKLAPITYP

¹⁴⁰

QGLAMAREIG

¹⁵⁰

SVKYLECSAL

¹⁶⁰

TQRGLKTVFD

¹⁷⁰

EAIRAVLG

Residue

Distance (Å)

GLY10

4.757

ASP11

3.840

GLY12

3.944

ALA13

3.632

VAL14

3.424

GLY15

3.084

LYS16

2.715

THR17

2.969

CYS18

2.820

LEU19

4.928

PHE28

3.520

PRO29

4.722

GLU31

4.984

TYR32

3.659

Residue

Distance (Å)

ILE33

4.418

PRO34

3.284

THR35

2.771

ASP57

4.823

THR58

4.158

ALA59

3.900

GLY60

2.780

GLN61

4.510

LYS116

3.037

ASP118

2.802

LEU119

3.478

SER158

3.500

ALA159

2.918

LEU160

3.239

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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). 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

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).

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Leucine-rich repeat kinase 2 (LRRK2)	PF16095 ; PF12799 ; PF13855 ; PF00069 ; PF08477 More >>	23.626 (43/182)	6.47E-07
ADP-ribosylation factor-like protein 4D (ARL4D)	PF00025	26.131 (52/199)	2.00E-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
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Ras signaling pathway	hsa04014	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Rap1 signaling pathway	hsa04015	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cAMP signaling pathway	hsa04024	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Chemokine signaling pathway	hsa04062	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Wnt signaling pathway	hsa04310	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Axon guidance	hsa04360	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
VEGF signaling pathway	hsa04370	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Focal adhesion	hsa04510	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Adherens junction	hsa04520	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Natural killer cell mediated cytotoxicity	hsa04650	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
B cell receptor signaling pathway	hsa04662	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Fc epsilon RI signaling pathway	hsa04664	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Regulation of actin cytoskeleton	hsa04810	Affiliated Target
Class: Cellular Processes => Cell motility	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	9	Degree centrality	9.67E-04	Betweenness centrality	1.09E-05
Closeness centrality	2.09E-01	Radiality	1.36E+01	Clustering coefficient	2.78E-02
Neighborhood connectivity	1.83E+01	Topological coefficient	1.48E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

Ras-related C3 Botulinum Toxin Substrate (Rac) and Src Family Kinases (SFK) Are Proximal and Essential for Phosphatidylinositol 3-Kinase (PI3K) Act... J Biol Chem. 2016 Mar 25;291(13):6912-22.

REF 2

Crystal Structure of the Human Rac3 in Complex with Gdp

REF 3

The crystal structure of the human RAC3 in complex with the CRIB domain of human p21-activated kinase 1 (PAK1).

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