7PBY

Crystal structure of CD73 in complex with 4-nitrocatechol in the open form

Summary for 7PBY

• Entry DOI: 10.2210/pdb7pby/pdb
• Descriptor: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: ecto-5'-nucleotidase, en, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 61023.58

Authors

Scaletti, E.R.,Strater, N. (deposition date: 2021-08-02, release date: 2021-10-13, Last modification date: 2024-10-16)

Primary citation

Scaletti, E.,Huschmann, F.U.,Mueller, U.,Weiss, M.S.,Strater, N.
Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5'-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives.
Purinergic Signal, 17:693-704, 2021

PubMed Abstract: Human ecto-5-nucleotidase (CD73) is involved in purinergic signalling, which influences a diverse range of biological processes. CD73 hydrolyses AMP and is the major control point for the levels of extracellular adenosine. Inhibitors of CD73 thus block the immunosuppressive action of adenosine, a promising approach for cancer immunotherapy. Interestingly, ADP and ATP are competitive inhibitors of CD73, with the most potent small-molecule inhibitors to date being non-hydrolysable ADP analogues. While AMP is the major substrate of the enzyme, CD73 has been reported to hydrolyse other 5'-nucleoside monophosphates. Based on a fragment screening campaign at the BESSY II synchrotron, we present the binding modes of various deoxyribo- and ribonucleoside monophosphates and of four additional fragments binding to the nucleoside binding site of the open form of the enzyme. Kinetic analysis of monophosphate hydrolysis shows that ribonucleotide substrates are favoured over their deoxyribose equivalents with AMP being the best substrate. We characterised the initial step of AMP hydrolysis, the binding mode of AMP to the open conformation of CD73 and compared that to other monophosphate substrates. In addition, the inhibitory activity of various bisphosphonic acid derivatives of nucleoside diphosphates was determined. Although AMPCP remains the most potent inhibitor, replacement of the adenine base with other purines or with pyrimidines increases the K value only between twofold and sixfold. On the other hand, these nucleobases offer new opportunities to attach substituents for improved pharmacological properties.

PubMed: 34403084
DOI: 10.1007/s11302-021-09802-w

Experimental method

X-RAY DIFFRACTION (1.13 Å)