Target Information

Target General Information

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Target ID

T24211 (Former ID: TTDI02289)

Target Name

C1 esterase inhibitor (SERPING1)

Synonyms

Serpin G1; SERPING1; Plasma protease C1 inhibitor; C1inhibiting factor; C1Inh; C1 Inh

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Gene Name

SERPING1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Innate/adaptive immunodeficiency [ICD-11: 4A00]

Sexual dysfunction [ICD-11: HA00-HA01]

Function

Activation of the C1 complex is under control of the C1- inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein. {ECO:0000269|PubMed:8495195}.

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BioChemical Class

Serpin protein

UniProt ID

IC1_HUMAN

Sequence

MASRLTLLTLLLLLLAGDRASSNPNATSSSSQDPESLQDRGEGKVATTVISKMLFVEPIL
EVSSLPTTNSTTNSATKITANTTDEPTTQPTTEPTTQPTIQPTQPTTQLPTDSPTQPTTG
SFCPGPVTLCSDLESHSTEAVLGDALVDFSLKLYHAFSAMKKVETNMAFSPFSIASLLTQ
VLLGAGENTKTNLESILSYPKDFTCVHQALKGFTTKGVTSVSQIFHSPDLAIRDTFVNAS
RTLYSSSPRVLSNNSDANLELINTWVAKNTNNKISRLLDSLPSDTRLVLLNAIYLSAKWK
TTFDPKKTRMEPFHFKNSVIKVPMMNSKKYPVAHFIDQTLKAKVGQLQLSHNLSLVILVP
QNLKHRLEDMEQALSPSVFKAIMEKLEMSKFQPTLLTLPRIKVTTSQDMLSIMEKLEFFD
FSYDLNLCGLTEDPDLQVSAMQHQTVLELTETGVEAAAASAISVARTLLVFEVQQPFLFV
LWDQQHKFPVFMGRVYDPRA

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Cinryze

Drug Info

Approved

Hereditary angioedema

[2]

Rhucin

Drug Info

Approved

Hereditary angioedema

[3], [4]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 2 Modulator drugs

Cinryze

Drug Info

[1]

Rhucin

Drug Info

[3], [4]

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: (2S,3R,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol

Ligand Info

Structure Description

Active human c1-inhibitor in complex with dextran sulfate

PDB:5DUQ

Method

X-ray diffraction

Resolution

2.90 Å

Mutation

[5]

PDB Sequence

STEAVLGDAL

¹²⁴

VDFSLKLYHA

¹³⁴

FSAMKKVETN

¹⁴⁴

MAFSPFSIAS

¹⁵⁴

LLTQVLLGAG

¹⁶⁴

ENTKTNLESI

¹⁷⁴

LSYPKDFTCV

¹⁸⁴

HQALKGFTTK

¹⁹⁴

GVTSVSQIFH

²⁰⁴

SPDLAIRDTF

²¹⁴

VNASRTLYSS

²²⁴

SPRVLSNNSD

²³⁴

ANLELINTWV

²⁴⁴

AKNTNNKISR

²⁵⁴

LLDSLPSDTR

²⁶⁴

LVLLNAIYLS

²⁷⁴

AKWKTTFDPK

²⁸⁴

KTRMEPFHFK

²⁹⁴

NSVIKVPMMN

³⁰⁴

SKKYPVAHFI

³¹⁴

DQTLKAKVGQ

³²⁴

LQLSHNLSLV

³³⁴

ILVPQNLKHR

³⁴⁴

LEDMEQALSP

³⁵⁴

SVFKAIMEKL

³⁶⁴

EMSKFQPTLL

³⁷⁴

TLPRIKVTTS

³⁸⁴

QDMLSIMEKL

³⁹⁴

EFFDFSYDLN

⁴⁰⁴

LCGLTEDPDL

⁴¹⁴

QVSAMQHQTV

⁴²⁴

LELTETGVEA

⁴³⁴

AAASAISVAR

⁴⁴⁴

TLLVFEVQQP

⁴⁵⁴

FLFMLWDQQH

⁴⁶⁴

KFPVFMGRVY

⁴⁷⁴

Residue

Distance (Å)

LYS284

3.327

Residue

Distance (Å)

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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	Pathway Map
Complement and coagulation cascades	hsa04610	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	2.73E-05
Closeness centrality	1.60E-01	Radiality	1.24E+01	Clustering coefficient	1.33E-01
Neighborhood connectivity	6.33E+00	Topological coefficient	2.73E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Co-Targets

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Co-Targets

Co-Targets Info

References

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REF 1

2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.

REF 2

Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of Type 2 Diabetes. Curr Drug Targets. 2009 Jan;10(1):71-87.

REF 3

Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.

REF 4

Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. BioDrugs. 2012 Oct 1;26(5):315-23.

REF 5

How Dextran Sulfate Affects C1-inhibitor Activity: A Model for Polysaccharide Potentiation. Structure. 2016 Dec 6;24(12):2182-2189.

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