7pby | pdb_00007pby

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

spinqualitylabelsall models 7pby, resolution 1.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7pby is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.13Å Ligands: 4NC, CA, DMS, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease 5NTD_HUMAN Hereditary arterial and articular multiple calcification syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function 5NTD_HUMAN Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities. Publication Abstract from PubMed 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 Ki value only between twofold and sixfold. On the other hand, these nucleobases offer new opportunities to attach substituents for improved pharmacological properties. Substrate binding modes of purine and pyrimidine nucleotides to human ecto-5'-nucleotidase (CD73) and inhibition by their bisphosphonic acid derivatives.,Scaletti E, Huschmann FU, Mueller U, Weiss MS, Strater N Purinergic Signal. 2021 Aug 17. pii: 10.1007/s11302-021-09802-w. doi:, 10.1007/s11302-021-09802-w. PMID:34403084 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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