4TMF
Crystal structure of human CD38 in complex with hydrolysed compound JMS713
Summary for 4TMF
| Entry DOI | 10.2210/pdb4tmf/pdb |
| Descriptor | 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) |
| Functional Keywords | cd38, adp-ribosyl cyclase, cyclic adp-ribose, x-crystallography, calcium signaling, inhibitory compound, jms713, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 60656.09 |
| Authors | Zhang, H.,Swarbrick, J.,Potter, B.,Hao, Q. (deposition date: 2014-06-01, release date: 2015-05-13, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 25226087DOI: 10.1021/jm501037u PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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