ADAM17

Target id: 1662

Nomenclature: ADAM17

Family: M12: Astacin/Adamalysin

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     ADAM17 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 824 2p25 ADAM17 ADAM metallopeptidase domain 17
Mouse - 846 12 A1.3 Adam17 a disintegrin and metallopeptidase domain 17
Rat - 827 6q16 Adam17 ADAM metallopeptidase domain 17
Previous and Unofficial Names
snake venom-like protease | TNF α convertase | TNF α-converting enzyme | TACE | tumor necrosis factor, alpha, converting enzyme | CD156B | cSVP
Database Links
Specialist databases
MEROPS M12.217 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of TACE in complex with IK682.
PDB Id:  2fv5
Ligand:  IK-862
Resolution:  2.1Å
Species:  Human
References:  6
Enzyme Reaction
EC Number: 3.4.24.86

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
IK-862 Hs Inhibition 9.3 pKi 3
pKi 9.3 (Ki 5.6x10-10 M) [3]
SL422 Pig Inhibition 7.9 pKi 8
pKi 7.9 (Ki 1.2x10-8 M) [8]
Description: Partially purified enzyme from pancreas.
BMS-561392 Hs Inhibition 8.7 pIC50 2
pIC50 8.7 (IC50 2x10-9 M) [2]
ilomastat Hs Inhibition 8.1 pIC50 7
pIC50 8.1 (IC50 7.5x10-9 M) [7]
Description: Measured in an in vitro assay.
apratastat Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 2x10-8 M) [4]
View species-specific inhibitor tables
Immunopharmacology Comments
The proteolytic activity of ADAM17 (a type I transmembrane metalloproteinase; a.k.a.TNF-alpha converting enzyme or TACE) is involved in the shedding of the extracellular domains of several transmembrane proteins e.g. cytokines (TNFα), growth factors, receptors (IL-6R and TNF-R for example) and adhesion molecules. Cleavage of substrates, including TNFα, IL-6R and L-selectin, produce pro-inflammatory effects stimulating both innate and acquired immune responses. ADAM17 activity is crucial during development (ADAM17 knockout is embryonic lethal), and it has been shown that the soluble IL-6R/IL-6 complex generates agonist-like signals in a process termed IL-6 trans-signaling. The generation and maintenance of several inflammatory and autoimmune diseases is driven by IL-6 trans-signaling [1]. ADAM17 activity may also be involved in directing migration of activated lymphocytes and neutrophils in vivo, by catalysing the shedding of L-selectin from the surface of leukocytes. ADAM17 is being investigated as a novel therapeutic target in immune-related diseases such as rheumatoid arthritis (RA) [5], but also plays roles in tissue regeneration and cancer development.
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  positive regulation of leukocyte chemotaxis (GO:0002690) IC
positive regulation of T cell chemotaxis (GO:0010820) IMP
References: 
Immuno Process:  T cell (activation)
Immuno Process ID:  4
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  germinal center formation (GO:0002467) ISS
T cell differentiation in thymus (GO:0033077) ISS
References: 
Immuno Process:  B cell (activation)
Immuno Process ID:  5
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  germinal center formation (GO:0002467) ISS
B cell differentiation (GO:0030183) ISS
References: 
Immuno Process:  Immune regulation
Immuno Process ID:  6
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  positive regulation of leukocyte chemotaxis (GO:0002690) IC
positive regulation of T cell chemotaxis (GO:0010820) IMP
regulation of mast cell apoptotic process (GO:0033025) ISS
References: 
Immuno Process:  Immune system development
Immuno Process ID:  8
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  B cell differentiation (GO:0030183) ISS
T cell differentiation in thymus (GO:0033077) ISS
spleen development (GO:0048536) ISS
References: 
Immuno Process:  Cytokine production & signalling
Immuno Process ID:  9
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  positive regulation of chemokine production (GO:0032722) IMP
tumor necrosis factor-mediated signaling pathway (GO:0033209) TAS
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  positive regulation of leukocyte chemotaxis (GO:0002690) IC
positive regulation of T cell chemotaxis (GO:0010820) IMP
positive regulation of chemokine production (GO:0032722) IMP
References: 
Immuno Process:  Cellular signalling
Immuno Process ID:  11
Comment: 
GO Annotation:  Associated to GO processes
GO Processes:  B cell differentiation (GO:0030183) ISS
T cell differentiation in thymus (GO:0033077) ISS
References: 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Inflammatory skin and bowel disease, neonatal, 1; NISBD1
Synonyms: Neonatal inflammatory skin and bowel disease [Orphanet: ORPHA294023]
OMIM: 614328
Orphanet: ORPHA294023

References

Show »

1. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. (2011) The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur. J. Cell Biol.90 (6-7): 484-94. [PMID:21145125]

2. DasGupta S, Murumkar PR, Giridhar R, Yadav MR. (2009) Current perspective of TACE inhibitors: a review. Bioorg. Med. Chem.17 (2): 444-59. [PMID:19095454]

3. Georgiadis D, Yiotakis A. (2008) Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. Bioorg. Med. Chem.16 (19): 8781-94. [PMID:18790648]

4. Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D et al.. (2006) Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg. Med. Chem. Lett.16 (6): 1605-9. [PMID:16426848]

5. Moss ML, Sklair-Tavron L, Nudelman R. (2008) Drug insight: tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis. Nat Clin Pract Rheumatol4 (6): 300-9. [PMID:18414459]

6. Niu X, Umland S, Ingram R, Beyer BM, Liu YH, Sun J, Lundell D, Orth P. (2006) IK682, a tight binding inhibitor of TACE. Arch. Biochem. Biophys.451 (1): 43-50. [PMID:16762314]

7. 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]

8. Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL et al.. (2001) Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo. J. Med. Chem.44 (16): 2636-60. [PMID:11472217]

How to cite this page

M12: Astacin/Adamalysin: ADAM17. Last modified on 31/01/2017. Accessed on 20/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1662.