Target Information

Target General Information

Target ID

T59230 (Former ID: TTDR00811)

Target Name

Estradiol 17 beta-dehydrogenase 4 (HSD17B4)

Synonyms

MFE-2; HSD17B4; DBP; D-bifunctional protein; 17-beta-hydroxysteroid dehydrogenase 4; 17-beta-HSD 4; 17 beta-hydroxysteroid dehydrogenase type 4

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Gene Name

HSD17B4

Target Type

Literature-reported target

[1]

Function

Bifunctional enzymeacting on the peroxisomal beta- oxidation pathway for fatty acids. Catalyzes the formation of 3- ketoacyl-CoA intermediates from both straight-chain and 2-methyl- branched-chain fatty acids.

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

DHB4_HUMAN

Sequence

MGSPLRFDGRVVLVTGAGAGLGRAYALAFAERGALVVVNDLGGDFKGVGKGSLAADKVVE
EIRRRGGKAVANYDSVEEGEKVVKTALDAFGRIDVVVNNAGILRDRSFARISDEDWDIIH
RVHLRGSFQVTRAAWEHMKKQKYGRIIMTSSASGIYGNFGQANYSAAKLGLLGLANSLAI
EGRKSNIHCNTIAPNAGSRMTQTVMPEDLVEALKPEYVAPLVLWLCHESCEENGGLFEVG
AGWIGKLRWERTLGAIVRQKNHPMTPEAVKANWKKICDFENASKPQSIQESTGSIIEVLS
KIDSEGGVSANHTSRATSTATSGFAGAIGQKLPPFSYAYTELEAIMYALGVGASIKDPKD
LKFIYEGSSDFSCLPTFGVIIGQKSMMGGGLAEIPGLSINFAKVLHGEQYLELYKPLPRA
GKLKCEAVVADVLDKGSGVVIIMDVYSYSEKELICHNQFSLFLVGSGGFGGKRTSDKVKV
AVAIPNRPPDAVLTDTTSLNQAALYRLSGDWNPLHIDPNFASLAGFDKPILHGLCTFGFS
ARRVLQQFADNDVSRFKAIKARFAKPVYPGQTLQTEMWKEGNRIHFQTKVQETGDIVISN
AYVDLAPTSGTSAKTPSEGGKLQSTFVFEEIGRRLKDIGPEVVKKVNAVFEWHITKGGNI
GAKWTIDLKSGSGKVYQGPAKGAADTTIILSDEDFMEVVLGKLDPQKAFFSGRLKARGNI
MLSQKLQMILKDYAKL

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3D Structure

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AlphaFold

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: Nicotinamide-Adenine-Dinucleotide

Ligand Info

Structure Description

Crystal Structure Of Human 17-Beta-Hydroxysteroid Dehydrogenase Type 4 In Complex With NAD

PDB:1ZBQ

Method

X-ray diffraction

Resolution

2.19 Å

Mutation

[3]

PDB Sequence

SPLRFDGRVV

¹²

LVTGAGAGLG

²²

RAYALAFAER

³²

GALVVVNDLG

⁴²

GDFKGVGKGS

⁵²

LAADKVVEEI

⁶²

RRRGGKAVAN

⁷²

YDSVEEGEKV

⁸²

VKTALDAFGR

⁹²

IDVVVNNAGI

¹⁰²

LRDRSFARIS

¹¹²

DEDWDIIHRV

¹²²

HLRGSFQVTR

¹³²

AAWEHMKKQK

¹⁴²

YGRIIMTSSA

¹⁵²

SGIYGNFGQA

¹⁶²

NYSAAKLGLL

¹⁷²

GLANSLAIEG

¹⁸²

RKSNIHCNTI

¹⁹²

APNAGSRMTQ

²⁰²

TVMPEDLVEA

²¹²

LKPEYVAPLV

²²²

LWLCHESCEE

²³²

NGGLFEVGAG

²⁴²

WIGKLRWERT

²⁵²

LGAIVRQKNH

²⁶²

PMTPEAVKAN

²⁷²

WKKICDFENA

²⁸²

SKPQSIQEST

²⁹²

GSIIEVLSKI

³⁰²

Residue

Distance (Å)

THR15

4.955

GLY16

3.403

ALA17

4.987

GLY18

4.070

ALA19

3.589

GLY20

3.469

LEU21

2.861

GLY22

4.436

ASN39

3.288

ASP40

2.406

LEU41

3.494

GLY42

4.023

GLY43

3.897

PHE45

4.255

ASP74

4.032

SER75

2.730

VAL76

3.158

GLU77

4.417

ASN99

2.878

Residue

Distance (Å)

ALA100

3.464

GLY101

3.370

ILE102

3.577

VAL122

3.857

HIS123

3.487

THR149

3.501

SER150

3.414

SER151

3.469

ALA152

4.955

TYR164

2.590

LYS168

2.868

PRO194

2.983

ASN195

3.297

ALA196

2.896

GLY197

4.998

SER198

2.458

ARG199

2.776

MET200

3.388

THR201

4.418

Ligand Name: Oxtoxynol-10

Ligand Info

Structure Description

LIGANDED STEROL CARRIER PROTEIN TYPE 2 (SCP-2) LIKE DOMAIN OF HUMAN MULTIFUNCTIONAL ENZYME TYPE 2 (MFE-2)

PDB:1IKT

Method

X-ray diffraction

Resolution

1.75 Å

Mutation

[4]

PDB Sequence

LQSTFVFEEI

¹⁵

GRRLKDIGPE

²⁵

VVKKVNAVFE

³⁵

WHITKGGNIG

⁴⁵

AKWTIDLKSG

⁵⁵

SGKVYQGPAK

⁶⁵

GAADTTIILS

⁷⁵

DEDFMEVVLG

⁸⁵

KLDPQKAFFS

⁹⁵

GRLKARGNIM

¹⁰⁵

LSQKLQMILK

¹¹⁵

DYAKL

Residue

Distance (Å)

ILE15

4.244

TRP36

3.609

ILE50

4.582

PHE79

3.714

VAL82

3.763

VAL83

3.850

PRO89

3.683

GLN90

3.113

PHE93

3.569

PHE94

3.932

Residue

Distance (Å)

LEU98

4.053

ALA100

4.707

ILE104

4.252

MET105

3.537

SER107

3.205

GLN108

2.954

LEU110

4.207

GLN111

3.181

LEU114

3.675

LYS115

3.990

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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
(3R)-3-hydroxyacyl-CoA dehydrogenase (HSD17B8)	PF13561	33.460 (88/263)	1.65E-24
Dehydrogenase/reductase SDR family member 4 (DHRS4)	PF13561	29.958 (71/237)	3.78E-16
3-oxoacyl-[acyl-carrier-protein] reductase (CBR4)	PF13561	32.673 (66/202)	1.50E-15
Dehydrogenase/reductase SDR family member 6 (BDH2)	PF13561	29.381 (57/194)	7.59E-15
Peroxisomal trans-2-enoyl-CoA reductase (PECR)	PF13561	29.648 (59/199)	2.38E-13
Dehydrogenase/reductase SDR family member 2, mitochondrial (DHRS2)	PF13561	26.316 (50/190)	8.20E-09
Peroxisomal 2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing] (DECR2)	PF13561	25.907 (50/193)	1.52E-08
L-xylulose reductase (DCXR)	PF13561	26.943 (52/193)	6.83E-08
Putative dehydrogenase/reductase SDR family member 4-like 1 (DHRS4L1)	PF13561	25.726 (62/241)	4.53E-07
17-beta-hydroxysteroid dehydrogenase 14 (HSD17B14)	PF13561	27.411 (54/197)	8.07E-04
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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
Primary bile acid biosynthesis	hsa00120	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Biosynthesis of unsaturated fatty acids	hsa01040	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy
Peroxisome	hsa04146	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy

Degree	16	Degree centrality	1.72E-03	Betweenness centrality	1.70E-04
Closeness centrality	1.95E-01	Radiality	1.33E+01	Clustering coefficient	5.67E-01
Neighborhood connectivity	2.10E+01	Topological coefficient	2.23E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Target Affiliated Biological Pathways

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BioCyc

[+] 1 BioCyc Pathways

Fatty acid beta-oxidation (peroxisome)

KEGG Pathway

[+] 3 KEGG Pathways

Primary bile acid biosynthesis

Metabolic pathways

Peroxisome

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Bile Acid Biosynthesis

WikiPathways

[+] 6 WikiPathways

Steroid Biosynthesis

alpha-linolenic (omega3) and linoleic (omega6) acid metabolism

Prostate Cancer

Peroxisomal beta-oxidation of tetracosanoyl-CoA

Peroxisomal lipid metabolism

Bile acid and bile salt metabolism

References

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REF 1

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 2

DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-41.

REF 3

Crystal Structure Of Human 17-Beta-Hydroxysteroid Dehydrogenase Type 4 In Complex With NAD

REF 4

Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution. J Mol Biol. 2001 Nov 9;313(5):1127-38.

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