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ADAM10

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Target id: 1658

Nomenclature: ADAM10

Family: M12: Astacin/Adamalysin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 748 15q21.3 ADAM10 ADAM metallopeptidase domain 10
Mouse 1 749 9 39.53 cM Adam10 a disintegrin and metallopeptidase domain 10
Rat 1 749 8q24 Adam10 ADAM metallopeptidase domain 10
Previous and Unofficial Names Click here for help
Kuzbanian protein homolog | Mammalian disintegrin-metalloprotease | CD156c | kuz | MADM | a disintegrin and metallopeptidase domain 10 | ADAM metallopeptidase domain 10 | HER-2 sheddase
Database Links Click here for help
Specialist databases
MEROPS M12.210 (Hs)
Other databases
Alphafold O14672 (Hs), O35598 (Mm), Q10743 (Rn)
BRENDA 3.4.24.81
CATH/Gene3D 3.40.390.10, 4.10.70.10
ChEMBL Target CHEMBL5028 (Hs)
Ensembl Gene ENSG00000137845 (Hs), ENSMUSG00000054693 (Mm), ENSRNOG00000054257 (Rn)
Entrez Gene 102 (Hs), 11487 (Mm), 29650 (Rn)
Human Protein Atlas ENSG00000137845 (Hs)
KEGG Enzyme 3.4.24.81
KEGG Gene hsa:102 (Hs), mmu:11487 (Mm), rno:29650 (Rn)
OMIM 602192 (Hs)
Orphanet ORPHA358659 (Hs)
Pharos O14672 (Hs)
RefSeq Nucleotide NM_001110 (Hs), NM_007399 (Mm), NM_019254 (Rn)
RefSeq Protein NP_001101 (Hs), NP_031425 (Mm), NP_062127 (Rn)
UniProtKB O14672 (Hs), O35598 (Mm), Q10743 (Rn)
Wikipedia ADAM10 (Hs)
Enzyme Reaction Click here for help
EC Number: 3.4.24.81

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
ilomastat Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pIC50 5
⤷ pIC50 8.1 (IC50 8.1x10-9 M) [5]
Description: Measured in an in vitro assay.
compound 25 [PMID: 18068976] Small molecule or natural product Primary target of this compound Hs Inhibition 7.8 pIC50 1
⤷ pIC50 7.8 (IC50 1.6x10-8 M) [1]
GI254023X Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 5.3 pIC50 3
⤷ pIC50 5.3 (IC50 5.3x10-6 M) [3]
Immunopharmacology Comments
ADAM10 has been identified as the primary physiologically relevant sheddase responsible for cleavage of ICOS ligand, and regulation of ICOS/ICOSL-dependent immune responses [4]. B cell ADAM10 inhibition represents a novel mechanism to modulate the ICOS/ICOSL pathway and alter the humoral immune response. Experimental evidence using patient-derived cells has identified ADAM10 as important for the shedding of soluble semaphorin 4D (Sema4D) from CD15+ granulocytes, a pathway implicated in the promotion of autoreactive antibody secretion by B cells that leads to the development of the autoimmune skin condition bullous pemphigoid [6].
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Reticulate acropigmentation of Kitamura; RAK
OMIM: 615537
Orphanet: ORPHA178307
General Comments
The proteolytic domains of ADAM10 and ADAM17 exhibit a high degree of homology, which explains their ability to cleave overlapping substrates. ADAM10 is responsible for cleaving a variety of substrates, including Notch receptors, delta-like 1, IL-6R, CXCL16, CD23 and ICOS ligand [2,4,7].

References

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1. Burns DM, He C, Li Y, Scherle P, Liu X, Marando CA, Covington MB, Yang G, Pan M, Turner S et al.. (2008) Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations. Bioorg Med Chem Lett, 18 (2): 560-4. [PMID:18068976]

2. Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R, Cichy J, Yagita H, Tew JG, Dempsey PJ, Crawford HC et al.. (2010) ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J Exp Med, 207 (3): 623-35. [PMID:20156974]

3. Hoettecke N, Ludwig A, Foro S, Schmidt B. (2010) Improved synthesis of ADAM10 inhibitor GI254023X. Neurodegener Dis, 7 (4): 232-8. [PMID:20197648]

4. Lownik JC, Luker AJ, Damle SR, Cooley LF, El Sayed R, Hutloff A, Pitzalis C, Martin RK, El Shikh MEM, Conrad DH. (2017) ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses. J Immunol, 199 (7): 2305-2315. [PMID:28814605]

5. Oh M, Im I, Lee YJ, Kim YH, Yoon JH, Park HG, Higashiyama S, Kim YC, Park WJ. (2004) Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors. Bioorg Med Chem Lett, 14 (24): 6071-4. [PMID:15546732]

6. Shen S, Ke Y, Dang E, Fang H, Chang Y, Zhang J, Zhu Z, Shao S, Qiao P, Zhang T et al.. (2018) Semaphorin 4D from CD15+ Granulocytes via ADAM10-Induced Cleavage Contributes to Antibody Production in Bullous Pemphigoid. J Invest Dermatol, 138 (3): 588-597. [PMID:29054606]

7. Weskamp G, Ford JW, Sturgill J, Martin S, Docherty AJ, Swendeman S, Broadway N, Hartmann D, Saftig P, Umland S et al.. (2006) ADAM10 is a principal 'sheddase' of the low-affinity immunoglobulin E receptor CD23. Nat Immunol, 7 (12): 1293-8. [PMID:17072319]

How to cite this page

M12: Astacin/Adamalysin: ADAM10. Last modified on 01/11/2018. Accessed on 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1658.