2pgl: Difference between revisions
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==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=''> | |||
== Structural highlights == | |||
<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='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='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='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> | |||
</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. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pg/2pgl_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=2pgl ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:17591784</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2pgl" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Cluster of Differentiation | *[[Cluster of Differentiation CD38|Cluster of Differentiation CD38]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Graeff | [[Category: Large Structures]] | ||
[[Category: Hao | [[Category: Graeff R]] | ||
[[Category: Kriksunov | [[Category: Hao Q]] | ||
[[Category: Lee | [[Category: Kriksunov IA]] | ||
[[Category: Liu | [[Category: Lee HC]] | ||
[[Category: Moreau | [[Category: Liu Q]] | ||
[[Category: Potter | [[Category: Moreau C]] | ||
[[Category: Potter BVL]] | |||
Latest revision as of 04:18, 21 November 2024
Catalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analogCatalysis associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog
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. 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 PubMedCyclic 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 AlsoReferences
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