9HJG
Crystal structure of human CD73 (ecto-5'-nucleotidase) in complex with an N6-disubstituted acyclic ADP analog (compound 26 in publication) in the closed state
This is a non-PDB format compatible entry.
Summary for 9HJG
| Entry DOI | 10.2210/pdb9hjg/pdb |
| Descriptor | 5'-nucleotidase, ZINC ION, [5-[2-chloranyl-6-[methyl-(phenylmethyl)amino]purin-9-yl]pentoxy-oxidanyl-phosphoryl]methylphosphonic acid, ... (5 entities in total) |
| Functional Keywords | nucleotide analog, dimetal center, closed state, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 244327.29 |
| Authors | Strater, N.,Moschuetz, S.,Federico, S.,Renn, C.,Muller, C.E. (deposition date: 2024-11-29, release date: 2025-05-28) |
| Primary citation | Federico, S.,Renn, C.,Brehova, P.,Janeba, Z.,Moschutz, S.,Sylvester, K.,Shamleh, R.A.,Baburi, H.,Zimmermann, H.,El-Tayeb, A.,Strater, N.,Muller, C.E. Acyclic purine and pyrimidine nucleotide analogs as ecto-5'-nucleotidase (CD73) inhibitors. Eur.J.Med.Chem., 294:117653-117653, 2025 Cited by PubMed Abstract: Ecto-5'-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the N-disubstituted acyclic ADP analog 26 (N-benzyl,N-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog 27 (N-benzyl,N-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (K 563 nM at soluble CD73; K 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs. PubMed: 40378575DOI: 10.1016/j.ejmech.2025.117653 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.31 Å) |
Structure validation
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