2i66

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[[Image:2i66.gif|left|200px]]
 
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{{Structure
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==Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis==
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|PDB= 2i66 |SIZE=350|CAPTION= <scene name='initialview01'>2i66</scene>, resolution 1.70&Aring;
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<StructureSection load='2i66' size='340' side='right'caption='[[2i66]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=G1R:[(2R,3R,4R,5R)-5-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+DIHYDROGEN+DIPHOSPHATE'>G1R</scene> and <scene name='pdbligand=G2R:[(2R,3R,4R,5R)-5-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL [(2R,3S,4S)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL DIHYDROGEN DIPHOSPHATE'>G2R</scene>
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<table><tr><td colspan='2'>[[2i66]] 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=2I66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2I66 FirstGlance]. <br>
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|ACTIVITY= [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]
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7&#8491;</td></tr>
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|GENE= CD38 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G1R:[(2R,3R,4R,5R)-5-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+DIHYDROGEN+DIPHOSPHATE'>G1R</scene>, <scene name='pdbligand=G2R:[(2R,3R,4R,5R)-5-(2-AMINO-6-OXO-1,6-DIHYDRO-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+[(2R,3S,4S)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL]METHYL+DIHYDROGEN+DIPHOSPHATE'>G2R</scene></td></tr>
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}}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2i66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i66 OCA], [https://pdbe.org/2i66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2i66 RCSB], [https://www.ebi.ac.uk/pdbsum/2i66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2i66 ProSAT]</span></td></tr>
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</table>
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'''Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis'''
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== Function ==
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[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.
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== Evolutionary Conservation ==
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==Overview==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i6/2i66_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2i66 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD(+)) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD(+) to synthesize two calcium-mobilizing molecules. By using NAD(+) and a surrogate substrate, NGD(+), we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu(226) rather than by a covalent linkage. The polar interactions between Glu(226) and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser(193) was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.
The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD(+)) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD(+) to synthesize two calcium-mobilizing molecules. By using NAD(+) and a surrogate substrate, NGD(+), we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu(226) rather than by a covalent linkage. The polar interactions between Glu(226) and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser(193) was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.
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==About this Structure==
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Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis.,Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q J Biol Chem. 2006 Oct 27;281(43):32861-9. Epub 2006 Sep 2. PMID:16951430<ref>PMID:16951430</ref>
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2I66 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I66 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis., Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q, J Biol Chem. 2006 Oct 27;281(43):32861-9. Epub 2006 Sep 2. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16951430 16951430]
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</div>
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<div class="pdbe-citations 2i66" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: NAD(+) nucleosidase]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Graeff R]]
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[[Category: Graeff, R.]]
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[[Category: Hao Q]]
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[[Category: Hao, Q.]]
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[[Category: Kriksunov IA]]
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[[Category: Kriksunov, I A.]]
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[[Category: Lee HC]]
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[[Category: Lee, H C.]]
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[[Category: Liu Q]]
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[[Category: Liu, Q.]]
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[[Category: Munshi C]]
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[[Category: Munshi, C.]]
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[[Category: G1R]]
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[[Category: G2R]]
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[[Category: reaction intermediate]]
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[[Category: reaction product]]
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[[Category: the catalytic pocket]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:25:54 2008''
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Current revision

Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis

PDB ID 2i66

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