| Structural highlights
9hj4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.06Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
5NTD_HUMAN Hereditary arterial and articular multiple calcification syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
5NTD_HUMAN Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities.[1]
Publication Abstract from PubMed
Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39) catalyzes the extracellular hydrolysis of ATP generating AMP, while ecto-5'-nucleotidase (CD73) further hydrolyzes AMP yielding immunosuppressive adenosine. 8-Butylthioadenosine 5'-monophosphate (8-BuS-AMP) was described as a CD39 inhibitor but has been poorly characterized. The standard CD39 antagonist ARL 67156 is not suitable for in vivo studies due to metabolic instability. In the present study, we optimized and upscaled the synthesis of 8-BuS-AMP and performed a comprehensive investigation of its properties. It behaves as a competitive inhibitor at human and mouse CD39, and additionally inhibits CD73. Docking studies using a homology model of human CD39 and determination of an atomic-resolution (1.06 A) cocrystal structure with human CD73 indicated the inhibitor's interactions within the substrate binding pockets and explained the compound's stability toward hydrolysis. 8-BuS-AMP is metabolically highly stable in human and mouse liver microsomes. It inhibited epsilon-adenosine formation from epsilon-ATP and epsilon-AMP in human synovial fluid and enhanced activation and proliferation of peripheral human T lymphocytes. Thus, 8-BuS-AMP is a recommended tool compound for studying purinergic signaling in vitro and in vivo, being superior to the standard CD39 inhibitor ARL 67156. Moreover, it may serve as a lead structure to develop drugs for the immunotherapy of cancer.
Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5'-Monophosphate.,Bi C, Mirza S, Baburi H, Schakel L, Winzer R, Moschutz S, Keetz K, Lopez V, Pelletier J, Sevigny J, Schulze Zur Wiesch J, Claff T, Tolosa E, Namasivayam V, Strater N, Muller CE ACS Pharmacol Transl Sci. 2025 Apr 3;8(5):1401-1415. doi: , 10.1021/acsptsci.5c00126. eCollection 2025 May 9. PMID:40370983[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Garavaglia S, Bruzzone S, Cassani C, Canella L, Allegrone G, Sturla L, Mannino E, Millo E, De Flora A, Rizzi M. The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism. Biochem J. 2011 Sep 20. PMID:21933152 doi:10.1042/BJ20111263
- ↑ Bi C, Mirza S, Baburi H, Schäkel L, Winzer R, Moschütz S, Keetz K, Lopez V, Pelletier J, Sévigny J, Schulze Zur Wiesch J, Claff T, Tolosa E, Namasivayam V, Sträter N, Müller CE. Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5'-Monophosphate. ACS Pharmacol Transl Sci. 2025 Apr 3;8(5):1401-1415. PMID:40370983 doi:10.1021/acsptsci.5c00126
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