Target Information

Target General Information

Target ID

T17427 (Former ID: TTDI02083)

Target Name

Platelet glycoprotein Ib alpha (CD42b)

Synonyms

Platelet glycoprotein Ib alpha chain; Glycoprotein Ibalpha; Glycocalicin; GPIbalpha; GPIbA; GPIb-alpha; GPIb alpha; GP-Ib alpha; Antigen CD42balpha; Antigen CD42b-alpha

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Gene Name

GP1BA

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Thrombosis [ICD-11: DB61-GB90]

Function

GP-Ib, a surface membrane protein of platelets, participates in the formation of platelet plugs by binding to the A1 domain of vWF, which is already bound to the subendothelium.

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UniProt ID

GP1BA_HUMAN

Sequence

MPLLLLLLLLPSPLHPHPICEVSKVASHLEVNCDKRNLTALPPDLPKDTTILHLSENLLY
TFSLATLMPYTRLTQLNLDRCELTKLQVDGTLPVLGTLDLSHNQLQSLPLLGQTLPALTV
LDVSFNRLTSLPLGALRGLGELQELYLKGNELKTLPPGLLTPTPKLEKLSLANNNLTELP
AGLLNGLENLDTLLLQENSLYTIPKGFFGSHLLPFAFLHGNPWLCNCEILYFRRWLQDNA
ENVYVWKQGVDVKAMTSNVASVQCDNSDKFPVYKYPGKGCPTLGDEGDTDLYDYYPEEDT
EGDKVRATRTVVKFPTKAHTTPWGLFYSWSTASLDSQMPSSLHPTQESTKEQTTFPPRWT
PNFTLHMESITFSKTPKSTTEPTPSPTTSEPVPEPAPNMTTLEPTPSPTTPEPTSEPAPS
PTTPEPTSEPAPSPTTPEPTSEPAPSPTTPEPTPIPTIATSPTILVSATSLITPKSTFLT
TTKPVSLLESTKKTIPELDQPPKLRGVLQGHLESSRNDPFLHPDFCCLLPLGFYVLGLFW
LLFASVVLILLLSWVGHVKPQALDSGQGAALTTATQTTHLELQRGRQVTVPRAWLLFLRG
SLPTFRSSLFLWVRPNGRVGPLVAGRRPSALSQGRGQDLLSTVSIRYSGHSL

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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

ZK-001

Drug Info

Phase 1/2

Thrombosis

[1]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

TGX-6B4

Drug Info

Preclinical

Thrombosis

[2]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 1 Modulator drugs

ZK-001

Drug Info

[1]

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: tyrosine O-sulfate

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF THE COMPLEX OF PLATELET RECEPTOR GPIB-ALPHA AND ALPHA-THROMBIN AT 2.6A

PDB:1P8V

Method

X-ray diffraction

Resolution

2.60 Å

Mutation

Yes

[4]

PDB Sequence

HPICEVSKVA

¹⁰

SHLEVNCDKR

²⁰

DLTALPPDLP

³⁰

KDTTILHLSE

⁴⁰

NLLYTFSLAT

⁵⁰

LMPYTRLTQL

⁶⁰

NLDRCELTKL

⁷⁰

QVDGTLPVLG

⁸⁰

TLDLSHNQLQ

⁹⁰

SLPLLGQTLP

¹⁰⁰

ALTVLDVSFN

¹¹⁰

RLTSLPLGAL

¹²⁰

RGLGELQELY

¹³⁰

LKGNELKTLP

¹⁴⁰

PGLLTPTPKL

¹⁵⁰

EKLSLANNNL

¹⁶⁰

TELPAGLLNG

¹⁷⁰

LENLDTLLLQ

¹⁸⁰

ENSLYTIPKG

¹⁹⁰

FFGSHLLPFA

²⁰⁰

FLHGNPWLCN

²¹⁰

CEILYFRRWL

²²⁰

QDNAENVYVW

²³⁰

KQGVDVKAMT

²⁴⁰

SNVASVQCDN

²⁵⁰

SDKFPVYKYP

²⁶⁰

GKGCPTLGDE

²⁷⁰

GDTDLDY

Residue

Distance (Å)

ASP274

3.586

LEU275

1.330

Residue

Distance (Å)

ASP277

1.328

TYR278

1.327

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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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Leucine-rich repeat and fibronectin type-III domain-containing protein 5 (LRFN5)	PF07679 ; PF13306	25.769 (67/260)	6.83E-11
X-ray radiation resistance-associated protein 1 (XRRA1)		33.333 (46/138)	1.44E-06
Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1)	PF12796 ; PF16095 ; PF00069 ; PF08477 More >>	31.677 (51/161)	1.03E-05
Geranylgeranyl transferase type-2 subunit alpha (RABGGTA)	PF01239 ; PF07711	36.508 (46/126)	6.59E-05
Dynein axonemal assembly factor 1 (DNAAF1)	PF14580	31.250 (40/128)	4.28E-04
Serine/threonine-protein kinase 11-interacting protein (STK11IP)	PF15904	35.345 (41/116)	6.74E-04
Imidazoline receptor 1 (IR1)	PF00787	35.455 (39/110)	1.00E-03
Microtubule-actin cross-linking factor 1, isoforms 6/7 (MACF1)	PF13499 ; PF02187 ; PF00435 More >>	39.837 (49/123)	1.00E-03
Leucine-rich repeat-containing protein 49 (LRRC49)	PF14580	32.000 (40/125)	1.00E-03
Platelet glycoprotein Ib beta chain (GP1BB)	PF01463	32.895 (25/76)	2.00E-03
Leucine-rich repeat protein 1 (LRR1)	PF12799	29.932 (44/147)	2.00E-03
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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
ECM-receptor interaction	hsa04512	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Platelet activation	hsa04611	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Hematopoietic cell lineage	hsa04640	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	10	Degree centrality	1.07E-03	Betweenness centrality	3.95E-04
Closeness centrality	2.12E-01	Radiality	1.37E+01	Clustering coefficient	1.78E-01
Neighborhood connectivity	1.95E+01	Topological coefficient	1.29E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

ECM-receptor interaction

Platelet activation

Hematopoietic cell lineage

Panther Pathway

[+] 1 Panther Pathways

Blood coagulation

PID Pathway

[+] 1 PID Pathways

Beta2 integrin cell surface interactions

Reactome

[+] 3 Reactome Pathways

Intrinsic Pathway of Fibrin Clot Formation

GP1b-IX-V activation signalling

Platelet Adhesion to exposed collagen

WikiPathways

[+] 4 WikiPathways

Platelet Aggregation (Plug Formation)

Platelet Adhesion to exposed collagen

GP1b-IX-V activation signalling

Formation of Fibrin Clot (Clotting Cascade)

References

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REF 1

Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis. Thromb Haemost. 2014 Feb;111(2):279-89.

REF 2

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015808)

REF 3

Antithrombotic effect of platelet glycoprotein Ib-blocking monoclonal antibody Fab fragments in nonhuman primates. Arterioscler Thromb Vasc Biol. 2000 May;20(5):1347-53.

REF 4

Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science. 2003 Jul 11;301(5630):222-6.

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