Target Information

Target General Information

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Target ID

T79326 (Former ID: TTDI02570)

Target Name

Ketohexokinase (KHK)

Synonyms

Hepatic fructokinase

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Gene Name

KHK

Target Type

Literature-reported target

[1]

Function

Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.

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BioChemical Class

Kinase

UniProt ID

KHK_HUMAN

EC Number

EC 2.7.1.3

Sequence

MEEKQILCVGLVVLDVISLVDKYPKEDSEIRCLSQRWQRGGNASNSCTVLSLLGAPCAFM
GSMAPGHVADFLVADFRRRGVDVSQVAWQSKGDTPSSCCIINNSNGNRTIVLHDTSLPDV
SATDFEKVDLTQFKWIHIEGRNASEQVKMLQRIDAHNTRQPPEQKIRVSVEVEKPREELF
QLFGYGDVVFVSKDVAKHLGFQSAEEALRGLYGRVRKGAVLVCAWAEEGADALGPDGKLL
HSDAFPPPRVVDTLGAGDTFNASVIFSLSQGRSVQEALRFGCQVAGKKCGLQGFDGIV

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3D Structure

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PDB

HIT2.0 ID

T93NTV

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: AMP-PNP

Ligand Info

Structure Description

Crystal structure of human ketohexokinase complexed to different sugar molecules

PDB:2HW1

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[2]

PDB Sequence

EKQILCVGLV

¹²

VLDVISLVDK

²²

YPKEDSEIRC

³²

LSQRWQRGGN

⁴²

ASNSCTVLSL

⁵²

LGAPCAFMGS

⁶²

MAPGHVADFV

⁷²

LDDLRRYSVD

⁸²

LRYTVFQTTG

⁹²

SVPIATVIIN

¹⁰²

EASGSRTILY

¹¹²

YDRSLPDVSA

¹²²

TDFEKVDLTQ

¹³²

FKWIHIEGRN

¹⁴²

ASEQVKMLQR

¹⁵²

IDAHNTRQPP

¹⁶²

EQKIRVSVEV

¹⁷²

EKPREELFQL

¹⁸²

FGYGDVVFVS

¹⁹²

KDVAKHLGFQ

²⁰²

SAEEALRGLY

²¹²

GRVRKGAVLV

²²²

CAWAEEGADA

²³²

LGPDGKLLHS

²⁴²

DAFPPPRVVD

²⁵²

TLGAGDTFNA

²⁶²

SVIFSLSQGR

²⁷²

SVQEALRFGC

²⁸²

QVAGKKCGLQ

²⁹²

GFDGIV

Residue

Distance (Å)

ARG108

2.875

ILE110

4.860

GLU173

4.556

ALA224

3.317

TRP225

3.824

ALA226

3.259

GLU227

3.961

GLY229

3.236

ALA230

3.956

ALA244

3.903

PHE245

4.483

PRO246

3.539

PRO247

4.528

Residue

Distance (Å)

VAL250

4.438

THR253

3.551

LEU254

3.707

GLY255

2.751

ALA256

3.616

GLY257

3.000

ASP258

3.304

PHE260

3.827

CYS282

3.266

ALA285

3.329

GLY286

4.395

CYS289

4.190

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: beta-D-fructofuranose

Ligand Info

Structure Description

Crystal structure of human ketohexokinase complexed to different sugar molecules

PDB:2HW1

Method

X-ray diffraction

Resolution

2.10 Å

Mutation

[2]

PDB Sequence

EKQILCVGLV

¹²

VLDVISLVDK

²²

YPKEDSEIRC

³²

LSQRWQRGGN

⁴²

ASNSCTVLSL

⁵²

LGAPCAFMGS

⁶²

MAPGHVADFV

⁷²

LDDLRRYSVD

⁸²

LRYTVFQTTG

⁹²

SVPIATVIIN

¹⁰²

EASGSRTILY

¹¹²

YDRSLPDVSA

¹²²

TDFEKVDLTQ

¹³²

FKWIHIEGRN

¹⁴²

ASEQVKMLQR

¹⁵²

IDAHNTRQPP

¹⁶²

EQKIRVSVEV

¹⁷²

EKPREELFQL

¹⁸²

FGYGDVVFVS

¹⁹²

KDVAKHLGFQ

²⁰²

SAEEALRGLY

²¹²

GRVRKGAVLV

²²²

CAWAEEGADA

²³²

LGPDGKLLHS

²⁴²

DAFPPPRVVD

²⁵²

TLGAGDTFNA

²⁶²

SVIFSLSQGR

²⁷²

SVQEALRFGC

²⁸²

QVAGKKCGLQ

²⁹²

GFDGIV

Residue

Distance (Å)

VAL13

3.492

ASP15

2.517

GLY40

3.558

GLY41

2.964

ASN42

2.717

ASN45

3.076

ALA97

3.484

Residue

Distance (Å)

ILE110

4.297

TYR112

3.425

GLU139

4.698

LYS174

4.938

LEU254

4.013

GLY255

4.424

ASP258

2.676

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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

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	Pathway Map
Fructose and mannose metabolism	hsa00051	Affiliated Target
Class: Metabolism => Carbohydrate metabolism	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	1.31E-04
Closeness centrality	1.68E-01	Radiality	1.26E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	8.50E+00	Topological coefficient	5.00E-01	Eccentricity	12
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

References

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REF 1

Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK). J Med Chem. 2017 Sep 28;60(18):7835-7849.

REF 2

Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr. 2009 Mar;65(Pt 3):201-11.

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