Target Information

Target General Information

Target ID

T99909 (Former ID: TTDI02086)

Target Name

Mortalin (HSPA9)

Synonyms

mt-HSP70; Stress-70 protein, mitochondrial; Peptide-binding protein 74; PBP74; MOT; Heat shock 70 kDa protein 9; HSPA9B; GRP75; GRP-75; 75 kDa glucose-regulated protein

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Gene Name

HSPA9

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Interacts with and stabilizes ISC cluster assembly proteins FXN, NFU1, NFS1 and ISCU. Regulates erythropoiesis via stabilization of ISC assembly. May play a role in the control of cell proliferation and cellular aging. Chaperone protein which plays an important role in mitochondrial iron-sulfur cluster (ISC) biogenesis.

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BioChemical Class

Heat shock protein

UniProt ID

GRP75_HUMAN

Sequence

MISASRAAAARLVGAAASRGPTAARHQDSWNGLSHEAFRLVSRRDYASEAIKGAVVGIDL
GTTNSCVAVMEGKQAKVLENAEGARTTPSVVAFTADGERLVGMPAKRQAVTNPNNTFYAT
KRLIGRRYDDPEVQKDIKNVPFKIVRASNGDAWVEAHGKLYSPSQIGAFVLMKMKETAEN
YLGHTAKNAVITVPAYFNDSQRQATKDAGQISGLNVLRVINEPTAAALAYGLDKSEDKVI
AVYDLGGGTFDISILEIQKGVFEVKSTNGDTFLGGEDFDQALLRHIVKEFKRETGVDLTK
DNMALQRVREAAEKAKCELSSSVQTDINLPYLTMDSSGPKHLNMKLTRAQFEGIVTDLIR
RTIAPCQKAMQDAEVSKSDIGEVILVGGMTRMPKVQQTVQDLFGRAPSKAVNPDEAVAIG
AAIQGGVLAGDVTDVLLLDVTPLSLGIETLGGVFTKLINRNTTIPTKKSQVFSTAADGQT
QVEIKVCQGEREMAGDNKLLGQFTLIGIPPAPRGVPQIEVTFDIDANGIVHVSAKDKGTG
REQQIVIQSSGGLSKDDIENMVKNAEKYAEEDRRKKERVEAVNMAEGIIHDTETKMEEFK
DQLPADECNKLKEEISKMRELLARKDSETGENIRQAASSLQQASLKLFEMAYKKMASERE
GSGSSGTGEQKEDQKEEKQ

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

MKT-077

Drug Info

Phase 2

Solid tumour/cancer

[1], [2], [3]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

MKT-077

Drug Info

[1], [2], [3]

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: Adenosine monophosphate

Ligand Info

Structure Description

Structure of Mortalin-NBD with adenosine-5'-monophosphate and thiodiphosphate

PDB:6PMT

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

[4]

PDB Sequence

AVVGIDLGTT

⁶³

NSCVAVMEGK

⁷³

QAKVLENAEG

⁸³

ARTTPSVVAF

⁹³

TADGERLVGM

¹⁰³

PAKRQAVTNP

¹¹³

NNTFYATKRL

¹²³

IGRRYDDPEV

¹³³

QKDIKNVPFK

¹⁴³

IVRASNGDAW

¹⁵³

VEAHGKLYSP

¹⁶³

SQIGAFVLMK

¹⁷³

MKETAENYLG

¹⁸³

HTAKNAVITV

¹⁹³

PAYFNDSQRQ

²⁰³

ATKDAGQISG

²¹³

LNVLRVINEP

²²³

TAAALAYGLD

²³³

KSEDKVIAVY

²⁴³

DLGGGTFDIS

²⁵³

ILEIQKGVFE

²⁶³

VKSTNGDTFL

²⁷³

GGEDFDQALL

²⁸³

RHIVKEFKRE

²⁹³

TGVDLTKDNM

³⁰³

ALQRVREAAE

³¹³

KAKCELSSSV

³²³

QTDINLPYLT

³³³

MDSSGPKHLN

³⁴³

MKLTRAQFEG

³⁵³

IVTDLIRRTI

³⁶³

APCQKAMQDA

³⁷³

EVSKSDIGEV

³⁸³

ILVGGMTRMP

³⁹³

KVQQTVQDLF

⁴⁰³

GRAPSKAVNP

⁴¹³

DEAVAIGAAI

⁴²³

QGGVLA

Residue

Distance (Å)

THR63

3.879

ASN64

3.556

LEU245

4.645

GLY246

3.600

GLY247

2.833

GLY248

4.831

GLY275

3.355

GLU276

4.099

ASP279

4.286

GLU313

2.951

Residue

Distance (Å)

LYS316

2.479

CYS317

3.366

SER320

2.621

GLY387

3.424

GLY388

3.016

MET389

2.948

ARG391

3.052

MET392

4.473

ASP414

3.582

Ligand Name: adenosine diphosphate

Ligand Info

Structure Description

Mortalin nucleotide binding domain in the ADP-bound state

PDB:6NHK

Method

X-ray diffraction

Resolution

2.78 Å

Mutation

[5]

PDB Sequence

AVVGIDLGTT

⁶³

NSCVAVMEGK

⁷³

QAKVLENAEG

⁸³

ARTTPSVVAF

⁹³

TADGERLVGM

¹⁰³

PAKRQAVTNP

¹¹³

NNTFYATKRL

¹²³

IGRRYDDPEV

¹³³

QKDIKNVPFK

¹⁴³

IVRASNGDAW

¹⁵³

VEAHGKLYSP

¹⁶³

SQIGAFVLMK

¹⁷³

MKETAENYLG

¹⁸³

HTAKNAVITV

¹⁹³

PAYFNDSQRQ

²⁰³

ATKDAGQISG

²¹³

LNVLRVINEP

²²³

TAAALAYGLD

²³³

KSEDKVIAVY

²⁴³

DLGGGTFDIS

²⁵³

ILEIQKGVFE

²⁶³

VKSTNGDTFL

²⁷³

GGEDFDQALL

²⁸³

RHIVKEFKRE

²⁹³

TGVDLTKDNM

³⁰³

ALQRVREAAE

³¹³

KAKCELSSSV

³²³

QTDINLPYLT

³³³

MDSSGPKHLN

³⁴³

MKLTRAQFEG

³⁵³

IVTDLIRRTI

³⁶³

APCQKAMQDA

³⁷³

EVSKSDIGEV

³⁸³

ILVGGMTRMP

³⁹³

KVQQTVQDLF

⁴⁰³

GRAPSKAVNP

⁴¹³

DEAVAIGAAI

⁴²³

QGGVLA

Residue

Distance (Å)

ASP59

3.920

GLY61

3.714

THR62

4.475

THR63

3.461

ASN64

2.550

SER65

4.880

GLY246

3.777

GLY247

3.266

GLY248

4.438

THR249

4.812

GLY275

3.945

GLU276

4.465

Residue

Distance (Å)

ASP279

4.059

GLU313

2.650

LYS316

2.887

CYS317

3.593

SER320

2.875

GLY387

3.837

GLY388

3.038

MET389

3.173

ARG391

3.290

MET392

4.574

PRO413

4.742

ASP414

2.764

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
RNA degradation	hsa03018	Affiliated Target
Class: Genetic Information Processing => Folding, sorting and degradation	Pathway Hierarchy

Degree	38	Degree centrality	4.08E-03	Betweenness centrality	6.51E-03
Closeness centrality	2.47E-01	Radiality	1.43E+01	Clustering coefficient	1.12E-01
Neighborhood connectivity	2.51E+01	Topological coefficient	4.36E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

RNA degradation

Tuberculosis

NetPath Pathway

[+] 2 NetPath Pathways

TSH Signaling Pathway

TCR Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Parkinson disease

Reactome

[+] 2 Reactome Pathways

Mitochondrial protein import

Regulation of HSF1-mediated heat shock response

WikiPathways

[+] 2 WikiPathways

Mitochondrial Protein Import

Parkin-Ubiquitin Proteasomal System pathway

References

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REF 1

Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res. 2000 Dec 15;60(24):6818-21.

REF 2

Mortalin sensitizes human cancer cells to MKT-077-induced senescence. Cancer Lett. 2007 Jul 18;252(2):259-69.

REF 3

Analogs of the Allosteric Heat Shock Protein 70 (Hsp70) Inhibitor, MKT-077, as Anti-Cancer Agents. ACS Med Chem Lett. 2013 Nov 14;4(11).

REF 4

Structure of the mortalin nucleotide binding domain in complex with adenosine monophosphate

REF 5

Biophysical Consequences of EVEN-PLUS Syndrome Mutations for the Function of Mortalin. J Phys Chem B. 2019 Apr 25;123(16):3383-3396.

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