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integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor)

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2443

Nomenclature: integrin, alpha 4 subunit (antigen CD49D, alpha 4 subunit of VLA-4 receptor)

Family: Integrins

Contents:

Quaternary Structure: Complexes
integrin α4β1
integrin α4β7
Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1032 2q31.3 ITGA4 integrin subunit alpha 4
Mouse 1 1039 2 47.38 cM Itga4 integrin alpha 4
Rat - - 3q24 Itga4 integrin subunit alpha 4
Previous and Unofficial Names Click here for help
CD49 antigen-like family member D | CD49D | integrin alpha-4 | lymphocyte Peyer patch adhesion molecules subunit alpha | integrin, alpha 4
Database Links Click here for help
Alphafold P13612 (Hs), Q00651 (Mm)
ChEMBL Target CHEMBL278 (Hs), CHEMBL2111481 (Mm)
DrugBank Target P13612 (Hs)
Ensembl Gene ENSG00000115232 (Hs), ENSMUSG00000027009 (Mm), ENSRNOG00000004861 (Rn)
Entrez Gene 3676 (Hs), 16401 (Mm), 311144 (Rn)
Human Protein Atlas ENSG00000115232 (Hs)
KEGG Gene hsa:3676 (Hs), mmu:16401 (Mm), rno:311144 (Rn)
OMIM 192975 (Hs)
Pharos P13612 (Hs)
RefSeq Nucleotide NM_000885 (Hs), NM_010576 (Mm)
RefSeq Protein NP_000876 (Hs), NP_034706 (Mm)
UniProtKB P13612 (Hs), Q00651 (Mm)
Wikipedia ITGA4 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
carotegrast methyl Small molecule or natural product Approved drug Immunopharmacology Ligand Hs Inhibition - - 1
⤷ [1]
carotegrast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - -
⤷
firategrast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - - 2
⤷ [2]
valategrast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - - 4
⤷ [4]
zaurategrast Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - - 7
⤷ [7]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
abrilumab Peptide Immunopharmacology Ligand Hs Inhibition 11.1 pKd 6
⤷ pKd 11.1 (Kd 9x10-12 M) [6]
Description: Binding affinity for α4β7 receptors expressed on the surface of HuT78 cells.
natalizumab Peptide Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition - - 5
⤷ [5]
Antibody Comments
Natalizumab targets heteromeric integrin receptors of which α4 is a subunit.
Immunopharmacology Comments
Integrin subunit alpha 4 is the alpha subunit of the α4β1 lymphocyte homing receptor. The cytoplasmic domain of α4 binds tightly to paxillin, a signaling adaptor protein, and this interaction promotes increased cell migration and inhibits cell spreading [3]. Paxillin binding to α4 is blocked by phopshorylation of Ser988 in the α4 cytoplasmic tail.
α4-containing integrins are the molecular target of the monoclonal antibody natalizumab which was the first migration-inhibitory biological drug to be approved for inflammatory diseases.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 5 GO processes
GO:0050900 leukocyte migration IBA
GO:0050901 leukocyte tethering or rolling IMP
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GO:0050904 diapedesis IEA
GO:1903238 positive regulation of leukocyte tethering or rolling IEA
GO:2000406 positive regulation of T cell migration IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0030183 B cell differentiation IC
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
click arrow to show/hide IEA associations
GO:1903238 positive regulation of leukocyte tethering or rolling IEA
GO:2000406 positive regulation of T cell migration IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0030183 B cell differentiation IC
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 6 GO processes
GO:0007159 leukocyte cell-cell adhesion IDA
GO:0050900 leukocyte migration IBA
GO:0050901 leukocyte tethering or rolling IMP
click arrow to show/hide IEA associations
GO:0050904 diapedesis IEA
GO:1903238 positive regulation of leukocyte tethering or rolling IEA
GO:2000406 positive regulation of T cell migration IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0030183 B cell differentiation IC
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:1990771 clathrin-dependent extracellular exosome endocytosis IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0071345 cellular response to cytokine stimulus IEA

References

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1. Fukase H, Kajioka T, Oikawa I, Ikeda N, Furuie H. (2020) AJM300, a novel oral antagonist of α4-integrin, sustains an increase in circulating lymphocytes: A randomised controlled trial in healthy male subjects. Br J Clin Pharmacol, 86 (3): 591-600. [PMID:31658381]

2. Grove RA, Shackelford S, Sopper S, Pirruccello S, Horrigan J, Havrdova E, Gold M, Graff O. (2013) Leukocyte counts in cerebrospinal fluid and blood following firategrast treatment in subjects with relapsing forms of multiple sclerosis. Eur J Neurol, 20 (7): 1032-42. [PMID:23419064]

3. Han J, Liu S, Rose DM, Schlaepfer DD, McDonald H, Ginsberg MH. (2001) Phosphorylation of the integrin alpha 4 cytoplasmic domain regulates paxillin binding. J Biol Chem, 276 (44): 40903-9. [PMID:11533025]

4. Hijazi Y, Welker H, Dorr AE, Tang JP, Blain R, Renzetti LM, Abbas R. (2004) Pharmacokinetics, safety, and tolerability of R411, a dual alpha4beta1-alpha4beta7 integrin antagonist after oral administration at single and multiple once-daily ascending doses in healthy volunteers. J Clin Pharmacol, 44 (12): 1368-78. [PMID:15545307]

5. No authors listed. (2004) Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody. Drugs R D, 5 (2): 102-7. [PMID:15293871]

6. Pan WJ, Hsu H, Rees WA, Lear SP, Lee F, Foltz IN, Rathanaswami P, Manchulenko K, Chan BM, Zhang M et al.. (2013) Pharmacology of AMG 181, a human anti-α4 β7 antibody that specifically alters trafficking of gut-homing T cells. Br J Pharmacol, 169 (1): 51-68. [PMID:23425116]

7. Wolf C, Sidhu J, Otoul C, Morris DL, Cnops J, Taubel J, Bennett B. (2013) Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study. PLoS One, 8 (3): e58438. [PMID:23472197]

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