Target Information

Target General Information

Target ID

T44057 (Former ID: TTDI03034)

Target Name

Aquaporin-1 (AQP1)

Synonyms

Water channel protein for red blood cells and kidney proximal tubule; Urine water channel; CHIP28; Aquaporin-CHIP; AQP-1

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Gene Name

AQP1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Lips/oral mucosa miscellaneous disorder [ICD-11: DA02]

Function

Forms a water-specific channel that provides the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient.

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BioChemical Class

Major intrinsic protein

UniProt ID

AQP1_HUMAN

Sequence

MASEFKKKLFWRAVVAEFLATTLFVFISIGSALGFKYPVGNNQTAVQDNVKVSLAFGLSI
ATLAQSVGHISGAHLNPAVTLGLLLSCQISIFRALMYIIAQCVGAIVATAILSGITSSLT
GNSLGRNDLADGVNSGQGLGIEIIGTLQLVLCVLATTDRRRRDLGGSAPLAIGLSVALGH
LLAIDYTGCGINPARSFGSAVITHNFSNHWIFWVGPFIGGALAVLIYDFILAPRSSDLTD
RVKVWTSGQVEEYDLDADDINSRVEMKPK

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3D Structure

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PDB

HIT2.0 ID

T75NEV

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

AAV-AQP1

Drug Info

Phase 1/2

Xerostomia

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

[14C]TEA

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: Cholesterol

Ligand Info

Structure Description

Erythrocyte ankyrin-1 complex class 2 local refinement of AQP1 (C4 symmetry applied)

PDB:7UZE

Method

Electron microscopy

Resolution

2.40 Å

Mutation

[3]

PDB Sequence

SEFKKKLFWR

¹²

AVVAEFLATT

²²

LFVFISIGSA

³²

LGFKYPVGNN

⁴²

QTAVQDNVKV

⁵²

SLAFGLSIAT

⁶²

LAQSVGHISG

⁷²

AHLNPAVTLG

⁸²

LLLSQISIFR

⁹³

ALMYIIAQCV

¹⁰³

GAIVATAILS

¹¹³

GITSSLTGNS

¹²³

LGRNDLADGV

¹³³

NSGQGLGIEI

¹⁴³

IGTLQLVLCV

¹⁵³

LATTDRRRRD

¹⁶³

LGGSAPLAIG

¹⁷³

LSVALGHLLA

¹⁸³

IDYTGCGINP

¹⁹³

ARSFGSAVIT

²⁰³

HNFSNHWIFW

²¹³

VGPFIGGALA

²²³

VLIYDFILAP

²³³

RSSDLTDRVK

²⁴³

VWTSGQ

Residue

Distance (Å)

ASN134

2.220

GLY136

2.411

GLN137

2.800

LEU139

3.178

GLY140

2.221

ILE141

4.819

Residue

Distance (Å)

ILE143

2.743

ILE144

2.226

LEU147

4.339

ILE218

4.389

LEU222

3.867

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Ligand Name: S-Palmitoyl-L-cysteine

Ligand Info

Structure Description

Erythrocyte ankyrin-1 complex class 2 local refinement of AQP1 (C4 symmetry applied)

PDB:7UZE

Method

Electron microscopy

Resolution

2.40 Å

Mutation

[3]

PDB Sequence

SEFKKKLFWR

¹²

AVVAEFLATT

²²

LFVFISIGSA

³²

LGFKYPVGNN

⁴²

QTAVQDNVKV

⁵²

SLAFGLSIAT

⁶²

LAQSVGHISG

⁷²

AHLNPAVTLG

⁸²

LLLSQISIFR

⁹³

ALMYIIAQCV

¹⁰³

GAIVATAILS

¹¹³

GITSSLTGNS

¹²³

LGRNDLADGV

¹³³

NSGQGLGIEI

¹⁴³

IGTLQLVLCV

¹⁵³

LATTDRRRRD

¹⁶³

LGGSAPLAIG

¹⁷³

LSVALGHLLA

¹⁸³

IDYTGCGINP

¹⁹³

ARSFGSAVIT

²⁰³

HNFSNHWIFW

²¹³

VGPFIGGALA

²²³

VLIYDFILAP

²³³

RSSDLTDRVK

²⁴³

VWTSGQ

Residue

Distance (Å)

LEU81

2.385

LEU83

3.248

LEU84

2.768

LEU85

2.335

SER86

1.329

GLN88

1.330

ILE89

3.399

VAL214

4.315

PHE217

2.395

ILE218

3.148

ALA221

2.298

Residue

Distance (Å)

LEU222

4.862

VAL224

2.618

LEU225

3.526

ASP228

4.807

PHE229

2.260

LEU238

2.309

ARG241

2.515

VAL242

3.132

VAL244

2.551

TRP245

2.196

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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 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 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 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 Pathway Affiliation

Biological Network Descriptors

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

KEGG Pathway	Pathway ID	Affiliated Target
Renin secretion	hsa04924	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Proximal tubule bicarbonate reclamation	hsa04964	Affiliated Target
Class: Organismal Systems => Excretory system	Pathway Hierarchy
Bile secretion	hsa04976	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	9.67E-02	Radiality	8.73E+00	Clustering coefficient	0.00E+00
Neighborhood connectivity	5.00E+00	Topological coefficient	1.00E+00	Eccentricity	16
Download	Click to Download the Full PPI Network of This Target

References

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REF 1

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: 688).

REF 2

Clinical pipeline report, company report or official report of MeiraGTx.

REF 3

Architecture of the human erythrocyte ankyrin-1 complex. Nat Struct Mol Biol. 2022 Jul;29(7):706-718.

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