9HJ4
Crystal structure of CD73 (ecto-5'-nucleotidase) complexed to 8-butylthioadenosine 5'monophosphate (compound 3 in publication) in the open enzyme state
This is a non-PDB format compatible entry.
Summary for 9HJ4
| Entry DOI | 10.2210/pdb9hj4/pdb |
| Descriptor | 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (7 entities in total) |
| Functional Keywords | cd73, 5'nucleotidase, dizinc center, nucleotide derivative, amp derivative, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 61358.06 |
| Authors | Strater, N.,Moschuetz, S.,Bi, C.,Muller, C.E. (deposition date: 2024-11-27, release date: 2025-05-28) |
| Primary citation | 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, C.E. Synthesis, Characterization, Interactions, and Immunomodulatory Function of Ectonucleotidase CD39/CD73 Inhibitor 8-Butylthioadenosine 5'-Monophosphate. Acs Pharmacol Transl Sci, 8:1401-1415, 2025 Cited by PubMed Abstract: 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 Å) 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 ε-adenosine formation from ε-ATP and ε-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. PubMed: 40370983DOI: 10.1021/acsptsci.5c00126 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.06 Å) |
Structure validation
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