Target Information

Target General Information

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Target ID

T17642 (Former ID: TTDI02462)

Target Name

Serine protease HTRA1 (HTRA1)

Synonyms

Serine protease 11; L56; High-temperature requirement A serine peptidase 1; HTRA1

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Gene Name

HTRA1

Target Type

Literature-reported target

[1]

Function

Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.

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BioChemical Class

Peptidase

UniProt ID

HTRA1_HUMAN

EC Number

EC 3.4.21.-

Sequence

MQIPRAALLPLLLLLLAAPASAQLSRAGRSAPLAAGCPDRCEPARCPPQPEHCEGGRARD
ACGCCEVCGAPEGAACGLQEGPCGEGLQCVVPFGVPASATVRRRAQAGLCVCASSEPVCG
SDANTYANLCQLRAASRRSERLHRPPVIVLQRGACGQGQEDPNSLRHKYNFIADVVEKIA
PAVVHIELFRKLPFSKREVPVASGSGFIVSEDGLIVTNAHVVTNKHRVKVELKNGATYEA
KIKDVDEKADIALIKIDHQGKLPVLLLGRSSELRPGEFVVAIGSPFSLQNTVTTGIVSTT
QRGGKELGLRNSDMDYIQTDAIINYGNSGGPLVNLDGEVIGINTLKVTAGISFAIPSDKI
KKFLTESHDRQAKGKAITKKKYIGIRMMSLTSSKAKELKDRHRDFPDVISGAYIIEVIPD
TPAEAGGLKENDVIISINGQSVVSANDVSDVIKRESTLNMVVRRGNEDIMITVIPEEIDP

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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: B-Octylglucoside

Ligand Info

Structure Description

HtrA1 catalytic domain, mutationally inactivated

PDB:3TJO

Method

X-ray diffraction

Resolution

2.30 Å

Mutation

Yes

[2]

PDB Sequence

MDPNSLRHKY

¹⁶⁹

NFIADVVEKI

¹⁷⁹

APAVVHIELF

¹⁸⁹

RKLPFSKREV

¹⁹⁹

PVASGSGFIV

²⁰⁹

SEDGLIVTNA

²¹⁹

HVVTNKHRVK

²²⁹

VELKNGATYE

²³⁹

AKIKDVDEKA

²⁴⁹

DIALIKIDHQ

²⁵⁹

GKLPVLLLGR

²⁶⁹

SSELRPGEFV

²⁷⁹

VAIGSPFSLQ

²⁸⁹

NTVTTGIVST

²⁹⁹

TQDYIQTDAI

³²²

INYGNAGGPL

³³²

VNLDGEVIGI

³⁴²

NTLKVTAGIS

³⁵²

FAIPSDKIKK

³⁶²

FLTESHDR

Residue

Distance (Å)

VAL209

3.358

SER210

3.356

LEU214

3.546

LEU364

3.700

Residue

Distance (Å)

THR365

3.843

HIS368

3.469

ASP369

3.608

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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 Similarity Proteins Human Tissue Distribution

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 Similarity Proteins

Human Tissue Distribution

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1)	PF09007 ; PF00595	31.884 (22/69)	5.00E-03


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.

References

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REF 1

HtrA serine proteases as potential therapeutic targets in cancer. Curr Cancer Drug Targets. 2009 Jun;9(4):451-68.

REF 2

Structural and functional analysis of HtrA1 and its subdomains. Structure. 2012 Jun 6;20(6):1040-50.

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