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ATPase family AAA domain containing 2

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Target not currently curated in GtoImmuPdb

Target id: 2719

Nomenclature: ATPase family AAA domain containing 2

Family: 3.6.1.3 ATPases

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1390 8q24.13 ATAD2 ATPase family AAA domain containing 2
Mouse - 1040 15 D1 Atad2 ATPase family, AAA domain containing 2
Rat - 1373 7q33 Atad2 ATPase family, AAA domain containing 2
Previous and Unofficial Names Click here for help
ATPase family, AAA domain containing 2 | ATPase family
Database Links Click here for help
Alphafold Q6PL18 (Hs), Q8CDM1 (Mm)
BRENDA 3.6.1.3
CATH/Gene3D 1.20.920.10
ChEMBL Target CHEMBL2150837 (Hs)
Ensembl Gene ENSG00000156802 (Hs), ENSMUSG00000022360 (Mm), ENSRNOG00000025604 (Rn)
Entrez Gene 29028 (Hs), 70472 (Mm), 314993 (Rn)
Human Protein Atlas ENSG00000156802 (Hs)
KEGG Enzyme 3.6.1.3
KEGG Gene hsa:29028 (Hs), mmu:70472 (Mm), rno:314993 (Rn)
OMIM 611941 (Hs)
Pharos Q6PL18 (Hs)
RefSeq Nucleotide NM_014109 (Hs), NM_027435 (Mm), NM_001134879 (Rn)
RefSeq Protein NP_054828 (Hs), NP_081711 (Mm), NP_001128351 (Rn)
SynPHARM 82674 (in complex with compound 33 [PMID: 26230603])
82521 (in complex with compound 60 [PMID: 26155854])
84269 (in complex with GSK8814)
84272 (in complex with GSK8814)
84270 (in complex with GSK8814)
UniProtKB Q6PL18 (Hs), Q8CDM1 (Mm)
Wikipedia ATAD2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human ATAD2 bromodomain in complex with 5-5- methoxypyridin-3-yl-3-methyl-8-piperidin-4-ylamino-1,2-dihydro-1,7- naphthyridin-2-one (compound 60).
PDB Id:  5A5R
Ligand:  compound 60 [PMID: 26155854]
Resolution:  2.01Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human ATAD2 bromodomain in complex with 4-(3R,4R) -4-(3-methyl-2-oxo-1,2-dihydro-1,7-naphthyridin-8-yl)aminopiperidin-3- yloxymethyl)-1-thiane-1,1-dione
PDB Id:  5A82
Ligand:  compound 33 [PMID: 26230603]
Resolution:  1.86Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human ATAD2 bromodomain in complex with 8-(((3R,4R,5S)-3-((4,4-difluorocyclohexyl)methoxy)-5-methoxypiperidin-4-yl)amino)-3-methyl-5-(5-methylpyridin-3-yl)-1,7-naphthyridin-2(1H)-one.
PDB Id:  5LJ0
Ligand:  GSK8814
Resolution:  1.82Å
Species:  Human
References:  2
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the bromodomain of ATAD2 with AZ13824374
PDB Id:  7Q6T
Ligand:  AZ13824374
Resolution:  2.05Å
Species:  Human
References:  8
Enzyme Reaction Click here for help
EC Number: 3.6.1.3

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
AZ13824374 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.9 pKd 8
⤷ pKd 8.9 [8]
Description: Binding affinity determined in a DiscoveRx BROMOscan assay
GSK8814 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.1 pKd 2
⤷ pKd 8.1 (Kd 8x10-9 M) [2]
Description: By isothermal titration calorimetry (ICT) assay.
GSK8814 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.9 pKi 2
⤷ pKi 8.9 (Ki 1.25x10-9 M) [2]
Description: By Bromosphere assay using full length endogenous protein.
AZ13824374 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.2 pIC50 8
⤷ pIC50 8.2 [8]
Description: Determined in a TR-FRET biochemical enzyme inhibition assay
GSK8814 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 2
⤷ pIC50 7.3 (IC50 5.01x10-8 M) [2]
Description: By TR-FRET assay.
compound 23 [PMID: 31398032] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.5 pIC50 1
⤷ pIC50 6.5 (IC50 3.16x10-7 M) [1]
Description: Measuring small-molecule competition using TR-FRET assay with ATAD2 construct 6 (Flag-6H-tev-ATAd2(981-1121) and the biotinylated triacetylated histone H4 peptide (SGRG-K(Ac)-GG-K(Ac)-GLG-K(Ac)-GGAKRHRKV-biotin).
compound 57 [PMID: 26155854] Small molecule or natural product Hs Inhibition 5.9 pIC50 5
⤷ pIC50 5.9 [5]
compound 60 [PMID: 26155854] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 5.9 pIC50 5
⤷ pIC50 5.9 [5]
compound 33 [PMID: 26230603] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 5.3 pIC50 3
⤷ pIC50 5.3 [3]
General Comments
This is a bromodomain-containing protein that is involved in chromatin modification [7]. Abnormally high levels of ATAD2 expression in a wide variety of unrelated patient cancer samples correlates with poor prognosis and disease recurrence [4,6,9]. Design of selective ATAD2 inhibitors as novel anti-cancer agents is being pursued [1,8].

References

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1. Bamborough P, Chung CW, Demont EH, Bridges AM, Craggs PD, Dixon DP, Francis P, Furze RC, Grandi P, Jones EJ et al.. (2019) A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification. J Med Chem, 62 (16): 7506-7525. [PMID:31398032]

2. Bamborough P, Chung CW, Demont EH, Furze RC, Bannister AJ, Che KH, Diallo H, Douault C, Grandi P, Kouzarides T et al.. (2016) A Chemical Probe for the ATAD2 Bromodomain. Angew Chem Int Ed Engl, 55 (38): 11382-6. [PMID:27530368]

3. Bamborough P, Chung CW, Furze RC, Grandi P, Michon AM, Sheppard RJ, Barnett H, Diallo H, Dixon DP, Douault C et al.. (2015) Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors. J Med Chem, 58 (15): 6151-78. [PMID:26230603]

4. Caron C, Lestrat C, Marsal S, Escoffier E, Curtet S, Virolle V, Barbry P, Debernardi A, Brambilla C, Brambilla E et al.. (2010) Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers. Oncogene, 29 (37): 5171-81. [PMID:20581866]

5. Demont EH, Chung CW, Furze RC, Grandi P, Michon AM, Wellaway C, Barrett N, Bridges AM, Craggs PD, Diallo H et al.. (2015) Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors. J Med Chem, 58 (14): 5649-73. [PMID:26155854]

6. Kalashnikova EV, Revenko AS, Gemo AT, Andrews NP, Tepper CG, Zou JX, Cardiff RD, Borowsky AD, Chen HW. (2010) ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res, 70 (22): 9402-12. [PMID:20864510]

7. Morozumi Y, Boussouar F, Tan M, Chaikuad A, Jamshidikia M, Colak G, He H, Nie L, Petosa C, de Dieuleveult M et al.. (2016) Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells. J Mol Cell Biol, 8 (4): 349-62. [PMID:26459632]

8. Winter-Holt JJ, Bardelle C, Chiarparin E, Dale IL, Davey PRJ, Davies NL, Denz C, Fillery SM, Guérot CM, Han F et al.. (2022) Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models. J Med Chem, 65 (4): 3306-3331. [PMID:35133824]

9. Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW. (2007) ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci USA, 104 (46): 18067-72. [PMID:17998543]

How to cite this page

3.6.1.3 ATPases: ATPase family AAA domain containing 2. Last modified on 15/03/2022. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2719.