6TVG
Human CD73 (ecto 5'-nucleotidase) in complex with AMPCP in the open state
Summary for 6TVG
| Entry DOI | 10.2210/pdb6tvg/pdb |
| Descriptor | 5'-nucleotidase, ecto (CD73), isoform CRA_a, ZINC ION, PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, ... (6 entities in total) |
| Functional Keywords | en, e5nt, ecto-nucleotidase, nucleotide, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 61083.45 |
| Authors | Scaletti, E.,Strater, N. (deposition date: 2020-01-09, release date: 2020-02-26, Last modification date: 2024-11-06) |
| Primary citation | Bhattarai, S.,Pippel, J.,Scaletti, E.,Idris, R.,Freundlieb, M.,Rolshoven, G.,Renn, C.,Lee, S.Y.,Abdelrahman, A.,Zimmermann, H.,El-Tayeb, A.,Muller, C.E.,Strater, N. 2-Substituted alpha , beta-Methylene-ADP Derivatives: Potent Competitive Ecto-5'-nucleotidase (CD73) Inhibitors with Variable Binding Modes. J.Med.Chem., 63:2941-2957, 2020 Cited by PubMed Abstract: CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5'--[(phosphonomethyl)phosphonic acid] (, ) being the most potent inhibitors with values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP () was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky -substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development. PubMed: 32045236DOI: 10.1021/acs.jmedchem.9b01611 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.48 Å) |
Structure validation
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