3u4h: Difference between revisions
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==CD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose template== | ==CD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose template== | ||
<StructureSection load='3u4h' size='340' side='right' caption='[[3u4h]], [[Resolution|resolution]] 1.88Å' scene=''> | <StructureSection load='3u4h' size='340' side='right'caption='[[3u4h]], [[Resolution|resolution]] 1.88Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3u4h]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3u4h]] 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=3U4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U4H FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.878Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C8R:8-AMINO-N1-CYCLIC+INOSINE+5-DIPHOSPHORIBOSE'>C8R</scene></td></tr> | |||
<tr id=' | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3u4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u4h OCA], [https://pdbe.org/3u4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3u4h RCSB], [https://www.ebi.ac.uk/pdbsum/3u4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3u4h ProSAT]</span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Graeff R]] | ||
[[Category: | [[Category: Hao Q]] | ||
[[Category: Lee HC]] | |||
[[Category: | [[Category: Liu Q]] | ||
[[Category: | |||
Latest revision as of 20:34, 1 November 2023
CD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose templateCD38 structure-based inhibitor design using the N1-cyclic inosine 5'-diphosphate ribose template
Structural highlights
FunctionCD38_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. Publication Abstract from PubMedFew inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-mobilizing second messenger cyclic adenosine 5'-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5'-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 microM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 microM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 microM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR "northern" ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5'-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 microM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design. CD38 Structure-Based Inhibitor Design Using the 1-Cyclic Inosine 5'-Diphosphate Ribose Template.,Moreau C, Liu Q, Graeff R, Wagner GK, Thomas MP, Swarbrick JM, Shuto S, Lee HC, Hao Q, Potter BV PLoS One. 2013 Jun 19;8(6):e66247. Print 2013. PMID:23840430[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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