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PDBsum entry 4tmf
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Hydrolase/hydrolase inhibitor
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PDB id
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4tmf
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References listed in PDB file
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Key reference
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Title
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Cyclic adenosine 5'-Diphosphate ribose analogs without a "southern" ribose inhibit ADP-Ribosyl cyclase-Hydrolase cd38.
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Authors
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J.M.Swarbrick,
R.Graeff,
H.Zhang,
M.P.Thomas,
Q.Hao,
B.V.Potter.
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Ref.
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J Med Chem, 2014,
57,
8517-8529.
[DOI no: ]
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PubMed id
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Abstract
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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.
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