7P9R

Crystal structure of CD73 in complex with GMP in the open form

7P9R の概要

• エントリーDOI: 10.2210/pdb7p9r/pdb
• 分子名称: 5'-nucleotidase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: ecto-5'-nucleotidase, en, substrate, gmp, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61090.55

構造登録者

Scaletti, E.R.,Strater, N. (登録日: 2021-07-27, 公開日: 2021-10-13, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.41 Å)