Target Information

Target General Information

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Target ID

T15139 (Former ID: TTDI00155)

Target Name

Phosphoglycerate dehydrogenase (PHGDH)

Synonyms

PGDH3; Malate dehydrogenase; D-3-phosphoglycerate dehydrogenase; 3-PGDH; 2-oxoglutarate reductase

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Gene Name

PHGDH

Target Type

Literature-reported target

[1]

Function

Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate and the reversible oxidation of (S)-malate to oxaloacetate.

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BioChemical Class

Short-chain dehydrogenases reductase

UniProt ID

SERA_HUMAN

EC Number

EC 1.1.1.95

Sequence

MAFANLRKVLISDSLDPCCRKILQDGGLQVVEKQNLSKEELIAELQDCEGLIVRSATKVT
ADVINAAEKLQVVGRAGTGVDNVDLEAATRKGILVMNTPNGNSLSAAELTCGMIMCLARQ
IPQATASMKDGKWERKKFMGTELNGKTLGILGLGRIGREVATRMQSFGMKTIGYDPIISP
EVSASFGVQQLPLEEIWPLCDFITVHTPLLPSTTGLLNDNTFAQCKKGVRVVNCARGGIV
DEGALLRALQSGQCAGAALDVFTEEPPRDRALVDHENVISCPHLGASTKEAQSRCGEEIA
VQFVDMVKGKSLTGVVNAQALTSAFSPHTKPWIGLAEALGTLMRAWAGSPKGTIQVITQG
TSLKNAGNCLSPAVIVGLLKEASKQADVNLVNAKLLVKEAGLNVTTSHSPAAPGEQGFGE
CLLAVALAGAPYQAVGLVQGTTPVLQGLNGAVFRPEVPLRRDLPLLLFRTQTSDPAMLPT
MIGLLAEAGVRLLSYQTSLVSDGETWHVMGISSLLPSLEAWKQHVTEAFQFHF

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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: NADH

Ligand Info

Structure Description

CRYSTAL STRUCTURE PHGDH IN COMPLEX WITH NADH AND 3-PHOSPHOGLYCERATE AT 1.77 A RESOLUTION

PDB:6CWA

Method

X-ray diffraction

Resolution

1.77 Å

Mutation

[2]

PDB Sequence

RKVLISDSLD

¹⁵

PCCRKILQDG

²⁵

GLQVVEKQNL

³⁵

SKEELIAELQ

⁴⁵

DCEGLIVRSA

⁵⁵

TKVTADVINA

⁶⁵

AEKLQVVGRA

⁷⁵

GTGVDNVDLE

⁸⁵

AATRKGILVM

⁹⁵

NTPNGNSLSA

¹⁰⁵

AELTCGMIMC

¹¹⁵

LARQIPQATA

¹²⁵

SMKDGKWERK

¹³⁵

KFMGTELNGK

¹⁴⁵

TLGILGLGRI

¹⁵⁵

GREVATRMQS

¹⁶⁵

FGMKTIGYDP

¹⁷⁵

IISPEVSASF

¹⁸⁵

GVQQLPLEEI

¹⁹⁵

WPLCDFITVH

²⁰⁵

TPLLPSTTGL

²¹⁵

LNDNTFAQCK

²²⁵

KGVRVVNCAR

²³⁵

GGIVDEGALL

²⁴⁵

RALQSGQCAG

²⁵⁵

AALDVFTEEP

²⁶⁵

PRDRALVDHE

²⁷⁵

NVISCPHLGA

²⁸⁵

STKEAQSRCG

²⁹⁵

EEIAVQFVD

Residue

Distance (Å)

THR77

2.842

GLY78

4.805

PRO98

4.257

ASN101

3.186

SER102

4.181

ALA105

3.687

LEU150

4.240

GLY151

3.600

LEU152

4.347

GLY153

3.310

ARG154

3.009

ILE155

2.996

GLY156

4.470

TYR173

3.408

ASP174

2.660

PRO175

3.294

ILE176

3.156

ILE177

4.504

Residue

Distance (Å)

HIS205

3.321

THR206

2.652

PRO207

3.392

LEU208

4.647

LEU209

4.109

SER211

3.888

THR212

3.422

LEU215

4.253

CYS233

3.056

ALA234

3.385

ARG235

3.330

ASP259

2.876

VAL260

3.806

HIS282

3.130

LEU283

4.375

GLY284

3.175

ALA285

3.171

Ligand Name: Nicotinamide-Adenine-Dinucleotide

Ligand Info

Structure Description

Crystal structure of human 3-phosphoglycerate dehydrogenase

PDB:2G76

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

[3]

PDB Sequence

LRKVLISDSL

¹⁴

DPCCRKILQD

²⁴

GGLQVVEKQN

³⁴

LSKEELIAEL

⁴⁴

QDCEGLIVRS

⁵⁴

ATKVTADVIN

⁶⁴

AAEKLQVVGR

⁷⁴

AGTGVDNVDL

⁸⁴

EAATRKGILV

⁹⁴

MNTPNGNSLS

¹⁰⁴

AAELTCGMIM

¹¹⁴

CLARQIPQAT

¹²⁴

ASMKDGKWER

¹³⁴

KKFMGTELNG

¹⁴⁴

KTLGILGLGR

¹⁵⁴

IGREVATRMQ

¹⁶⁴

SFGMKTIGYD

¹⁷⁴

PIISPEVSAS

¹⁸⁴

FGVQQLPLEE

¹⁹⁴

IWPLCDFITV

²⁰⁴

HTPLLPSTTG

²¹⁴

LLNDNTFAQC

²²⁴

KKGVRVVNCA

²³⁴

RGGIVDEGAL

²⁴⁴

LRALQSGQCA

²⁵⁴

GAALDVFTEE

²⁶⁴

PPRDRALVDH

²⁷⁴

ENVISCPHLG

²⁸⁴

ASTKEAQSRC

²⁹⁴

GEEIAVQFVD

³⁰⁴

Residue

Distance (Å)

THR77

2.771

GLY78

4.618

PRO98

4.208

ASN101

3.732

SER102

4.445

ALA105

3.722

LEU150

4.162

GLY151

3.496

LEU152

4.325

GLY153

3.420

ARG154

2.906

ILE155

2.913

GLY156

4.414

TYR173

3.294

ASP174

2.661

PRO175

3.307

ILE176

3.924

ILE177

4.229

Residue

Distance (Å)

HIS205

3.398

THR206

2.623

PRO207

3.363

LEU208

4.519

LEU209

4.226

SER211

3.226

THR212

3.484

LEU215

4.174

CYS233

2.982

ALA234

3.428

ARG235

3.269

ILE238

4.973

ASP259

2.812

VAL260

3.841

HIS282

3.161

LEU283

4.395

GLY284

3.113

ALA285

3.212

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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

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
Glycine, serine and threonine metabolism	hsa00260	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy
Cysteine and methionine metabolism	hsa00270	Affiliated Target
Class: Metabolism => Amino acid metabolism	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	1.26E-04
Closeness centrality	1.75E-01	Radiality	1.28E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	6.33E+00	Topological coefficient	3.33E-01	Eccentricity	13
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

Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015 Feb 20;10(2):510-6.

REF 2

Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis. J Med Chem. 2019 Sep 12;62(17):7976-7997.

REF 3

Crystal structure of human 3-phosphoglycerate dehydrogenase

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