Target Information

Target General Information

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Target ID

T71081 (Former ID: TTDI02547)

Target Name

GTPase HRas (HRAS)

Synonyms

p21ras; cHras; c-H-ras; Transforming protein p21; HaRas; Ha-Ras; H-Ras-1; GTPase HRas, Nterminally processed

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Gene Name

HRAS

Target Type

Literature-reported target

[1]

Function

Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Involved in the activation of Ras protein signal transduction.

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BioChemical Class

Small GTPase

UniProt ID

RASH_HUMAN

Sequence

MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG
QEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNKCDL
AARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPG
CMSCKCVLS

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3D Structure

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PDB

HIT2.0 ID

T32YN4

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: 5'-Guanosine-Diphosphate-Monothiophosphate

Ligand Info

Structure Description

Monobody 12VC3 Bound to HRAS(WT)

PDB:7L0F

Method

X-ray diffraction

Resolution

1.98 Å

Mutation

[2]

PDB Sequence

MTEYKLVVVG

¹⁰

AGGVGKSALT

²⁰

IQLIQNHFVD

³⁰

EYDPTIEDSY

⁴⁰

RKQVVIDGET

⁵⁰

CLLDILDTAG

⁶⁰

QEEYSAMRDQ

⁷⁰

YMRTGEGFLC

⁸⁰

VFAINNTKSF

⁹⁰

EDIHQYREQI

¹⁰⁰

KRVKDSDDVP

¹¹⁰

MVLVGNKCDL

¹²⁰

AARTVESRQA

¹³⁰

QDLARSYGIP

¹⁴⁰

YIETSAKTRQ

¹⁵⁰

GVEDAFYTLV

¹⁶⁰

REIRQH

Residue

Distance (Å)

GLY10

4.900

ALA11

4.093

GLY12

3.853

GLY13

2.995

VAL14

3.215

GLY15

2.997

LYS16

2.511

SER17

2.883

ALA18

2.764

LEU19

4.934

PHE28

3.264

VAL29

2.686

ASP30

2.805

GLU31

3.698

TYR32

3.128

ASP33

4.363

Residue

Distance (Å)

PRO34

3.683

THR35

2.798

ASP57

4.601

THR58

4.147

ALA59

3.980

GLY60

3.152

ASN116

3.081

LYS117

3.381

CYS118

4.860

ASP119

2.790

LEU120

3.662

THR144

4.586

SER145

3.350

ALA146

2.937

LYS147

3.600

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Ligand Name: Guanosine-5'-Diphosphate

Ligand Info

Structure Description

CRYSTAL STRUCTURE ANALYSIS OF A FLUORESCENT FORM OF H-RAS P21 IN COMPLEX WITH GDP

PDB:2CE2

Method

X-ray diffraction

Resolution

1.00 Å

Mutation

Yes

[3]

PDB Sequence

MTEYKLVVVG

¹⁰

AGGVGKSALT

²⁰

IQLIQNHFVD

³⁰

ECDPTIEDSY

⁴⁰

RKQVVIDGET

⁵⁰

CLLDILDTAG

⁶⁰

QEEYSAMRDQ

⁷⁰

YMRTGEGFLC

⁸⁰

VFAINNTKSF

⁹⁰

EDIHQYREQI

¹⁰⁰

KRVKDSDDVP

¹¹⁰

MVLVGNKSDL

¹²⁰

AARTVESRQA

¹³⁰

QDLARSYGIP

¹⁴⁰

YIETSAKTRQ

¹⁵⁰

GVEDAFYTLV

¹⁶⁰

REIRQH

Residue

Distance (Å)

ALA11

3.969

GLY12

4.025

GLY13

2.932

VAL14

3.431

GLY15

3.003

LYS16

2.720

SER17

3.003

ALA18

2.841

PHE28

3.042

VAL29

3.244

ASP30

2.910

GLU31

3.839

Residue

Distance (Å)

CYS32

3.557

PRO34

4.786

ASP57

4.655

ASN116

3.042

LYS117

2.939

SER118

4.939

ASP119

2.907

LEU120

3.386

THR144

4.546

SER145

3.506

ALA146

2.768

LYS147

3.687

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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 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
ADP-ribosylation factor-like protein 4A (ARL4A)	PF00025	23.729 (28/118)	1.30E-06
ADP-ribosylation factor-like protein 4D (ARL4D)	PF00025	26.154 (34/130)	4.34E-05
ADP-ribosylation factor-like protein 4C (ARL4C)	PF00025	23.022 (32/139)	4.38E-04
Leucine-rich repeat kinase 2 (LRRK2)	PF16095 ; PF12799 ; PF13855 ; PF00069 ; PF08477 More >>	22.436 (35/156)	4.39E-04
ADP-ribosylation factor-like protein 8B (ARL8B)	PF00025	25.620 (31/121)	5.66E-04
ADP-ribosylation factor-like protein 14 (ARL14)	PF00025	21.387 (37/173)	1.00E-03
ADP-ribosylation factor-like protein 9 (ARL9)	PF00025	22.500 (27/120)	2.00E-03
ADP-ribosylation factor-like protein 8A (ARL8A)	PF00025	23.140 (28/121)	4.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


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
ErbB signaling pathway	hsa04012	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
Chemokine signaling pathway	hsa04062	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
FoxO signaling pathway	hsa04068	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Mitophagy - animal	hsa04137	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Autophagy - animal	hsa04140	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Endocytosis	hsa04144	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
mTOR signaling pathway	hsa04150	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Longevity regulating pathway	hsa04211	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Longevity regulating pathway - multiple species	hsa04213	Affiliated Target
Class: Organismal Systems => Aging	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	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
Apelin signaling pathway	hsa04371	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Focal adhesion	hsa04510	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Gap junction	hsa04540	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Signaling pathways regulating pluripotency of stem cells	hsa04550	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
C-type lectin receptor signaling pathway	hsa04625	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
JAK-STAT signaling pathway	hsa04630	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Natural killer cell mediated cytotoxicity	hsa04650	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	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
Thermogenesis	hsa04714	Affiliated Target
Class: Organismal Systems => Environmental adaptation	Pathway Hierarchy
Long-term potentiation	hsa04720	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Neurotrophin signaling pathway	hsa04722	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Cholinergic synapse	hsa04725	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Long-term depression	hsa04730	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Regulation of actin cytoskeleton	hsa04810	Affiliated Target
Class: Cellular Processes => Cell motility	Pathway Hierarchy
Insulin signaling pathway	hsa04910	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH signaling pathway	hsa04912	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Estrogen signaling pathway	hsa04915	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Melanogenesis	hsa04916	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Prolactin signaling pathway	hsa04917	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Thyroid hormone signaling pathway	hsa04919	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Oxytocin signaling pathway	hsa04921	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Relaxin signaling pathway	hsa04926	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
GnRH secretion	hsa04929	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Growth hormone synthesis, secretion and action	hsa04935	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	107	Degree centrality	1.15E-02	Betweenness centrality	1.24E-02
Closeness centrality	2.70E-01	Radiality	1.46E+01	Clustering coefficient	8.27E-02
Neighborhood connectivity	3.19E+01	Topological coefficient	2.50E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

References

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REF 1

HRAS as a potential therapeutic target of salirasib RAS inhibitor in bladder cancer. Int J Oncol. 2018 Aug;53(2):725-736.

REF 2

Selective and noncovalent targeting of RAS mutants for inhibition and degradation. Nat Commun. 2021 May 11;12(1):2656.

REF 3

A newly designed microspectrofluorometer for kinetic studies on protein crystals in combination with x-ray diffraction. Biophys J. 2006 Aug 1;91(3):981-92.

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