2i66: Difference between revisions

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[[Image:2i66.gif|left|200px]]


{{Structure
==Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis==
|PDB= 2i66 |SIZE=350|CAPTION= <scene name='initialview01'>2i66</scene>, resolution 1.70&Aring;
<StructureSection load='2i66' size='340' side='right'caption='[[2i66]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|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>, <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>
<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>
|ACTIVITY= <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='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>
|GENE= CD38 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<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>
|DOMAIN=
<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>
|RELATEDENTRY=[[2i65|2I65]], [[2i67|2I67]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i66 OCA], [http://www.ebi.ac.uk/pdbsum/2i66 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i66 RCSB]</span>
== 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.
 
== Evolutionary Conservation ==
'''Structural Basis for the Mechanistic Understanding Human CD38 Controlled Multiple Catalysis'''
[[Image:Consurf_key_small.gif|200px|right]]
 
Check<jmol>
 
  <jmolCheckbox>
==Overview==
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i6/2i66_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== 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.


==About this Structure==
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>
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].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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]
</div>
<div class="pdbe-citations 2i66" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: NAD(+) nucleosidase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Graeff R]]
[[Category: Graeff, R.]]
[[Category: Hao Q]]
[[Category: Hao, Q.]]
[[Category: Kriksunov IA]]
[[Category: Kriksunov, I A.]]
[[Category: Lee HC]]
[[Category: Lee, H C.]]
[[Category: Liu Q]]
[[Category: Liu, Q.]]
[[Category: Munshi C]]
[[Category: Munshi, C.]]
[[Category: reaction intermediate]]
[[Category: reaction product]]
[[Category: the catalytic pocket]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:40:15 2008''
Retrieved from "https://proteopedia.org/2i66"