4TMF

Crystal structure of human CD38 in complex with hydrolysed compound JMS713

4TMF の概要

• エントリーDOI: 10.2210/pdb4tmf/pdb
• 分子名称: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, 5-O-[(R)-{[(S)-[4-(8-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)butoxy](hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]-alpha-D- ribofuranose (3 entities in total)
• 機能のキーワード: cd38, adp-ribosyl cyclase, cyclic adp-ribose, x-crystallography, calcium signaling, inhibitory compound, jms713, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60656.09

構造登録者

Zhang, H.,Swarbrick, J.,Potter, B.,Hao, Q. (登録日: 2014-06-01, 公開日: 2015-05-13, 最終更新日: 2024-11-20)

主引用文献

Swarbrick, J.M.,Graeff, R.,Zhang, H.,Thomas, M.P.,Hao, Q.,Potter, B.V.
Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38.
J.Med.Chem., 57:8517-8529, 2014

PubMed Abstract: Cyclic adenosine 5'-diphosphate ribose (cADPR) analogs based on the cyclic inosine 5'-diphosphate ribose (cIDPR) template were synthesized by recently developed stereo- and regioselective N1-ribosylation. Replacing the base N9-ribose with a butyl chain generates inhibitors of cADPR hydrolysis by the human ADP-ribosyl cyclase CD38 catalytic domain (shCD38), illustrating the nonessential nature of the "southern" ribose for binding. Butyl substitution generally improves potency relative to the parent cIDPRs, and 8-amino-N9-butyl-cIDPR is comparable to the best noncovalent CD38 inhibitors to date (IC50 = 3.3 μM). Crystallographic analysis of the shCD38:8-amino-N9-butyl-cIDPR complex to a 2.05 Å resolution unexpectedly reveals an N1-hydrolyzed ligand in the active site, suggesting that it is the N6-imino form of cADPR that is hydrolyzed by CD38. While HPLC studies confirm ligand cleavage at very high protein concentrations, they indicate that hydrolysis does not occur under physiological concentrations. Taken together, these analogs confirm that the "northern" ribose is critical for CD38 activity and inhibition, provide new insight into the mechanism of cADPR hydrolysis by CD38, and may aid future inhibitor design.

PubMed: 25226087
DOI: 10.1021/jm501037u

実験手法

X-RAY DIFFRACTION (2.05 Å)