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| | ==Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog== | | ==Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog== |
| - | <StructureSection load='2pgl' size='340' side='right' caption='[[2pgl]], [[Resolution|resolution]] 1.76Å' scene=''> | + | <StructureSection load='2pgl' size='340' side='right'caption='[[2pgl]], [[Resolution|resolution]] 1.76Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2pgl]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PGL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2PGL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2pgl]] 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=2PGL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2PGL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N1C:N1-CYCLIC+INOSINE+5-DIPHOSPHORIBOSE'>N1C</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.76Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2pgj|2pgj]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N1C:N1-CYCLIC+INOSINE+5-DIPHOSPHORIBOSE'>N1C</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CD38 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2pgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pgl OCA], [https://pdbe.org/2pgl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2pgl RCSB], [https://www.ebi.ac.uk/pdbsum/2pgl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2pgl ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_nucleosidase NAD(+) nucleosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.5 3.2.2.5] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2pgl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pgl OCA], [http://pdbe.org/2pgl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2pgl RCSB], [http://www.ebi.ac.uk/pdbsum/2pgl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2pgl ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Graeff, R]] | + | [[Category: Large Structures]] |
| - | [[Category: Hao, Q]] | + | [[Category: Graeff R]] |
| - | [[Category: Kriksunov, I A]] | + | [[Category: Hao Q]] |
| - | [[Category: Lee, H C]] | + | [[Category: Kriksunov IA]] |
| - | [[Category: Liu, Q]] | + | [[Category: Lee HC]] |
| - | [[Category: Moreau, C]] | + | [[Category: Liu Q]] |
| - | [[Category: Potter, B V.L]] | + | [[Category: Moreau C]] |
| - | [[Category: Conformational changes of the active site]]
| + | [[Category: Potter BVL]] |
| - | [[Category: Human cd38 e226q mutant bound with n1-cidpr]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Substrate analog binding]]
| + | |
| - | [[Category: The catalytic pocket]]
| + | |
| Structural highlights
Function
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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Cyclic ADP-ribose (cADPR) is a calcium mobilization messenger important for mediating a wide range of physiological functions. The endogenous levels of cADPR in mammalian tissues are primarily controlled by CD38, a multifunctional enzyme capable of both synthesizing and hydrolyzing cADPR. In this study, a novel non-hydrolyzable analog of cADPR, N1-cIDPR (N1-cyclic inosine diphosphate ribose), was utilized to elucidate the structural determinants involved in the hydrolysis of cADPR. N1-cIDPR inhibits CD38-catalyzed cADPR hydrolysis with an IC(50) of 0.26 mM. N1-cIDPR forms a complex with CD38 or its inactive mutant in which the catalytic residue Glu-226 is mutated. Both complexes have been determined by x-ray crystallography at 1.7 and 1.76 A resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 A) with Glu-226, confirming our previously proposed model for cADPR catalysis. Structural analyses reveal that both the enzyme and substrate cADPR undergo catalysis-associated conformational changes. From the enzyme side, residues Glu-146, Asp-147, and Trp-125 work collaboratively to facilitate the formation of the Michaelis complex. From the substrate side, cADPR is found to change its conformation to fit into the active site until it reaches the catalytic residue. The binary CD38-cADPR model described here represents the most detailed description of the CD38-catalyzed hydrolysis of cADPR at atomic resolution. Our structural model should provide insights into the design of effective cADPR analogs.
Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog.,Liu Q, Kriksunov IA, Moreau C, Graeff R, Potter BV, Lee HC, Hao Q J Biol Chem. 2007 Aug 24;282(34):24825-32. Epub 2007 Jun 25. PMID:17591784[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liu Q, Kriksunov IA, Moreau C, Graeff R, Potter BV, Lee HC, Hao Q. Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog. J Biol Chem. 2007 Aug 24;282(34):24825-32. Epub 2007 Jun 25. PMID:17591784 doi:http://dx.doi.org/10.1074/jbc.M701653200
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