Target Information

Target General Information

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Target ID

T99397

Target Name

Voltage-dependent anion-selective channel 1 (VDAC1)

Synonyms

Porin 31HM; Porin 31HL; Plasmalemmal porin; Outer mitochondrial membrane protein porin 1

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Gene Name

VDAC1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Epidermal dysplasias [ICD-11: EK90]

Function

Forms a channel through the mitochondrial outer membrane and also the plasma membrane. The channel at the outer mitochondrial membrane allows diffusion of small hydrophilic molecules; in the plasma membrane it is involved in cell volume regulation and apoptosis. It adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV. The open state has a weak anion selectivity whereas the closed state is cation-selective (PubMed:11845315, PubMed:18755977, PubMed:20230784, PubMed:8420959). May participate in the formation of the permeability transition pore complex (PTPC) responsible for the release of mitochondrial products that triggers apoptosis (PubMed:15033708, PubMed:25296756).

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BioChemical Class

Eukaryotic mitochondrial porin

UniProt ID

VDAC1_HUMAN

Sequence

MAVPPTYADLGKSARDVFTKGYGFGLIKLDLKTKSENGLEFTSSGSANTETTKVTGSLET
KYRWTEYGLTFTEKWNTDNTLGTEITVEDQLARGLKLTFDSSFSPNTGKKNAKIKTGYKR
EHINLGCDMDFDIAGPSIRGALVLGYEGWLAGYQMNFETAKSRVTQSNFAVGYKTDEFQL
HTNVNDGTEFGGSIYQKVNKKLETAVNLAWTAGNSNTRFGIAAKYQIDPDACFSAKVNNS
SLIGLGYTQTLKPGIKLTLSALLDGKNVNAGGHKLGLGLEFQA

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3D Structure

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PDB

HIT2.0 ID

T11FY2

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

VDA-1102

Drug Info

Phase 2

Actinic keratosis

[1]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

VDA-1102

Drug Info

[1]

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: NADH

Ligand Info

Structure Description

NOE based model of hVDAC-1 bound to beta-NADH in detergent micelles

PDB:6TIR

Method

Solution NMR

Resolution

N.A.

Mutation

[2]

PDB Sequence

MAVPPTYADL

¹⁰

GKSARDVFTK

²⁰

GYGFGLIKLD

³⁰

LKTKSENGLE

⁴⁰

FTSSGSANTE

⁵⁰

TTKVTGSLET

⁶⁰

KYRWTEYGLT

⁷⁰

FTEKWNTDNT

⁸⁰

LGTEITVEDQ

⁹⁰

LARGLKLTFD

¹⁰⁰

SSFSPNTGKK

¹¹⁰

NAKIKTGYKR

¹²⁰

EHINLGCDMD

¹³⁰

FDIAGPSIRG

¹⁴⁰

ALVLGYEGWL

¹⁵⁰

AGYQMNFETA

¹⁶⁰

KSRVTQSNFA

¹⁷⁰

VGYKTDEFQL

¹⁸⁰

HTNVNDGTEF

¹⁹⁰

GGSIYQKVNK

²⁰⁰

KLETAVNLAW

²¹⁰

TAGNSNTRFG

²²⁰

IAAKYQIDPD

²³⁰

ACFSAKVNNS

²⁴⁰

SLIGLGYTQT

²⁵⁰

LKPGIKLTLS

²⁶⁰

ALLDGKNVNA

²⁷⁰

GGHKLGLGLE

²⁸⁰

FQALE

Residue

Distance (Å)

ARG15

2.341

VAL17

4.472

PHE18

2.190

THR19

2.473

LYS20

2.254

TYR22

2.596

GLN154

4.681

ASN168

4.890

ASN183

3.428

ASN185

2.660

GLU189

4.856

ASN207

3.244

ARG218

1.945

Residue

Distance (Å)

GLY220

3.067

ILE221

3.361

ALA222

3.056

LYS236

2.451

VAL237

2.399

ASN238

1.937

ASN239

4.699

SER240

4.421

LEU242

2.744

ILE243

4.176

GLY244

3.219

LEU262

1.967

Ligand Name: Spermidine

Ligand Info

Structure Description

Crystal structure of human voltage-dependent anion channel 1 (hVDAC1) in C222 space group

PDB:5XDO

Method

X-ray diffraction

Resolution

3.10 Å

Mutation

[3]

PDB Sequence

MAVPPTYADL

¹⁰

GKSARDVFTK

²⁰

GYGFGLIKLD

³⁰

LKTKSENGLE

⁴⁰

FTSSGSANTE

⁵⁰

TTKVTGSLET

⁶⁰

KYRWTEYGLT

⁷⁰

FTEKWNTDNT

⁸⁰

LGTEITVEDQ

⁹⁰

LARGLKLTFD

¹⁰⁰

SSFSPNTGKK

¹¹⁰

NAKIKTGYKR

¹²⁰

EHINLGCDMD

¹³⁰

FDIAGPSIRG

¹⁴⁰

ALVLGYEGWL

¹⁵⁰

AGYQMNFETA

¹⁶⁰

KSRVTQSNFA

¹⁷⁰

VGYKTDEFQL

¹⁸⁰

HTNVNDGTEF

¹⁹⁰

GGSIYQKVNK

²⁰⁰

KLETAVNLAW

²¹⁰

TAGNSNTRFG

²²⁰

IAAKYQIDPD

²³⁰

ACFSAKVNNS

²⁴⁰

SLIGLGYTQT

²⁵⁰

LKPGIKLTLS

²⁶⁰

ALLDGKNVNA

²⁷⁰

GGHKLGLGLE

²⁸⁰

FQA

Residue

Distance (Å)

TYR7

3.528

ALA8

4.346

LEU10

3.609

ARG15

4.555

GLN154

3.123

ASN168

4.680

Residue

Distance (Å)

HIS181

3.860

THR182

4.565

ASN183

3.503

GLY191

4.516

GLY192

4.425

SER193

4.281

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

There is no similarity protein (E value < 0.005) for this target


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
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cGMP-PKG signaling pathway	hsa04022	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Necroptosis	hsa04217	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
NOD-like receptor signaling pathway	hsa04621	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Cholesterol metabolism	hsa04979	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	28	Degree centrality	3.01E-03	Betweenness centrality	2.92E-03
Closeness centrality	2.27E-01	Radiality	1.40E+01	Clustering coefficient	1.14E-01
Neighborhood connectivity	1.68E+01	Topological coefficient	6.15E-02	Eccentricity	10
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 10 KEGG Pathways	+
1	Calcium signaling pathway
2	cGMP-PKG signaling pathway
3	Necroptosis
4	Cellular senescence
5	NOD-like receptor signaling pathway
6	Cholesterol metabolism
7	Parkinson disease
8	Huntington disease
9	Influenza A
10	Human T-cell leukemia virus 1 infection

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

The Structural Basis for Low Conductance in the Membrane Protein VDAC upon beta-NADH Binding and Voltage Gating. Structure. 2020 Feb 4;28(2):206-214.e4.

REF 3

Crystal structural characterization reveals novel oligomeric interactions of human voltage-dependent anion channel 1. Protein Sci. 2017 Sep;26(9):1749-1758.

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