Target Information

Target General Information

Target ID

T70518 (Former ID: TTDI02232)

Target Name

S-nitrosoglutathione reductase (CBR1)

Synonyms

ProstaglandinE(2) 9reductase; Prostaglandin 9ketoreductase; NADPHdependent carbonyl reductase 1; Carbonyl reductase [NADPH] 1; CBR1; 15hydroxyprostaglandin dehydrogenase [NADP(+)]

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Gene Name

CBR1

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Asthma [ICD-11: CA23]

Function

NADPH-dependent reductase with broad substratespecificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol. Can convert prostaglandin E2 to prostaglandin F2-alpha. Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione.

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

CBR1_HUMAN

EC Number

EC 1.1.1.184

Sequence

MSSGIHVALVTGGNKGIGLAIVRDLCRLFSGDVVLTARDVTRGQAAVQQLQAEGLSPRFH
QLDIDDLQSIRALRDFLRKEYGGLDVLVNNAGIAFKVADPTPFHIQAEVTMKTNFFGTRD
VCTELLPLIKPQGRVVNVSSIMSVRALKSCSPELQQKFRSETITEEELVGLMNKFVEDTK
KGVHQKEGWPSSAYGVTKIGVTVLSRIHARKLSEQRKGDKILLNACCPGWVRTDMAGPKA
TKSPEEGAETPVYLALLPPDAEGPHGQFVSEKRVEQW

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3D Structure

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PDB

HIT2.0 ID

T01JSX

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

N6022

Drug Info

Phase 2

Asthma

[1]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

N6022

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: Glutathione

Ligand Info

Structure Description

Crystal structure of human Carbonyl Reductase 1 in complex with glutathione

PDB:3BHJ

Method

X-ray diffraction

Resolution

1.77 Å

Mutation

[2]

PDB Sequence

SGIHVALVTG

¹¹

GNKGIGLAIV

²¹

RDLCRLFSGD

³¹

VVLTARDVTR

⁴¹

GQAAVQQLQA

⁵¹

EGLSPRFHQL

⁶¹

DIDDLQSIRA

⁷¹

LRDFLRKEYG

⁸¹

GLDVLVNNAG

⁹¹

IAFKVADPTP

¹⁰¹

FHIQAEVTMK

¹¹¹

TNFFGTRDVC

¹²¹

TELLPLIKPQ

¹³¹

GRVVNVSSIM

¹⁴¹

SVRALKSCSP

¹⁵¹

ELQQKFRSET

¹⁶¹

ITEEELVGLM

¹⁷¹

NKFVEDTKKG

¹⁸¹

VHQKEGWPSS

¹⁹¹

AYGVTKIGVT

²⁰¹

VLSRIHARKL

²¹¹

SEQRKGDKIL

²²¹

LNACCPGWVR

²³¹

TDMAGPKATK

²⁴¹

SPEEGAETPV

²⁵¹

YLALLPPDAE

²⁶¹

GPHGQFVSEK

²⁷¹

RVEQW

Residue

Distance (Å)

ALA93

4.170

PHE94

2.958

LYS95

3.438

VAL96

2.940

ALA97

4.515

PHE102

3.410

GLN105

2.805

THR109

4.834

Residue

Distance (Å)

MET141

4.943

SER190

3.708

SER191

3.482

ALA192

2.896

TYR193

2.841

MET234

3.486

ALA235

3.834

GLY236

4.998

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Ligand Name: NADPH

Ligand Info

Structure Description

Crystal structure of human CBR1 in complex with Hydroxy-PP

PDB:1WMA

Method

X-ray diffraction

Resolution

1.24 Å

Mutation

[3]

PDB Sequence

SGIHVALVTG

¹¹

GNKGIGLAIV

²¹

RDLCRLFSGD

³¹

VVLTARDVTR

⁴¹

GQAAVQQLQA

⁵¹

EGLSPRFHQL

⁶¹

DIDDLQSIRA

⁷¹

LRDFLRKEYG

⁸¹

GLDVLVNNAG

⁹¹

IAFKVADPTP

¹⁰¹

FHIQAEVTMK

¹¹¹

TNFFGTRDVC

¹²¹

TELLPLIKPQ

¹³¹

GRVVNVSSIM

¹⁴¹

SVRALKSCSP

¹⁵¹

ELQQKFRSET

¹⁶¹

ITEEELVGLM

¹⁷¹

NKFVEDTKKG

¹⁸¹

VHQKEGWPSS

¹⁹¹

AYGVTKIGVT

²⁰¹

VLSRIHARKL

²¹¹

SEQRKGDKIL

²²¹

LNACCPGWVR

²³¹

TDMAGPKATK

²⁴¹

SPEEGAETPV

²⁵¹

YLALLPPDAE

²⁶¹

GPHGQFVSEK

²⁷¹

RVEQW

Residue

Distance (Å)

GLY11

3.263

GLY12

3.964

ASN13

2.793

LYS14

3.435

GLY15

3.481

ILE16

2.853

GLY17

4.365

ARG37

2.800

ASP38

4.575

ARG41

4.128

LEU61

3.528

ASP62

2.968

ILE63

3.031

ASP64

3.400

ASN89

2.790

ALA90

3.539

GLY91

3.565

Residue

Distance (Å)

ILE92

3.574

THR112

3.849

VAL137

3.408

SER138

3.253

SER139

3.729

TYR193

2.686

LYS197

2.879

CYS226

3.752

PRO227

3.490

GLY228

3.021

TRP229

3.456

VAL230

2.862

THR232

2.667

ASP233

3.678

MET234

3.513

ALA235

3.628

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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

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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Peroxisomal trans-2-enoyl-CoA reductase (PECR)	PF13561	31.944 (46/144)	2.17E-08
Dehydrogenase/reductase SDR family member 4 (DHRS4)	PF13561	36.782 (32/87)	2.48E-05
Dehydrogenase/reductase SDR family member 2, mitochondrial (DHRS2)	PF13561	30.935 (43/139)	1.02E-04
3-oxoacyl-[acyl-carrier-protein] reductase (CBR4)	PF13561	25.214 (59/234)	1.72E-04


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
Arachidonic acid metabolism	hsa00590	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Folate biosynthesis	hsa00790	Affiliated Target
Class: Metabolism => Metabolism of cofactors and vitamins	Pathway Hierarchy
Metabolism of xenobiotics by cytochrome P450	hsa00980	Affiliated Target
Class: Metabolism => Xenobiotics biodegradation and metabolism	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	3.88E-04
Closeness centrality	1.76E-01	Radiality	1.29E+01	Clustering coefficient	5.00E-01
Neighborhood connectivity	1.00E+01	Topological coefficient	3.05E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target