View source for 4tmf


==Crystal structure of human CD38 in complex with hydrolysed compound JMS713==
<StructureSection load='4tmf' size='340' side='right'caption='[[4tmf]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4tmf]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TMF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TMF FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JS2:5-O-[(R)-{[(S)-[4-(8-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)BUTOXY](HYDROXY)PHOSPHORYL]OXY}(HYDROXY)PHOSPHORYL]-ALPHA-D-RIBOFURANOSE'>JS2</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tmf OCA], [https://pdbe.org/4tmf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tmf RCSB], [https://www.ebi.ac.uk/pdbsum/4tmf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tmf ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CD38_HUMAN CD38_HUMAN] Synthesizes cyclic ADP-ribose, a second messenger for glucose-induced insulin secretion. Also has cADPr hydrolase activity. Also moonlights as a receptor in cells of the immune system.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 muM). Crystallographic analysis of the shCD38:8-amino-N9-butyl-cIDPR complex to a 2.05 A 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.

Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38.,Swarbrick JM, Graeff R, Zhang H, Thomas MP, Hao Q, Potter BV J Med Chem. 2014 Oct 23;57(20):8517-29. doi: 10.1021/jm501037u. Epub 2014 Oct 1. PMID:25226087<ref>PMID:25226087</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4tmf" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hao Q]]
[[Category: Potter B]]
[[Category: Swarbrick J]]
[[Category: Zhang H]]