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Article: Dynamic conformations of the CD38-mediated NAD cyclization captured in a single crystal

TitleDynamic conformations of the CD38-mediated NAD cyclization captured in a single crystal
Authors
KeywordsADP-ribose
ADPR
ara-2′F-ADPR
ara-2′F-NAD
arabinosyl-2′-fluoro-deoxy-adenosine diphosphate-ribose
arabinosyl-2′-fluoro-deoxy-nicotinamide adenine dinucleotide
cADPR
cyclic ADP-ribose
PDB
Protein Data Bank
Issue Date2011
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
Citation
Journal Of Molecular Biology, 2011, v. 405 n. 4, p. 1070-1078 How to Cite?
AbstractThe extracellular domain of human CD38 is a multifunctional enzyme involved in the metabolism of two Ca2+ messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. When NAD is used as substrate, CD38 predominantly hydrolyzes it to ADP-ribose, with a trace amount of cyclic ADP-ribose produced through cyclization of the substrate. However, mutation of a key residue at the active site, E146, inhibits the hydrolysis activity of CD38 but greatly increases its cyclization activity. To understand the role of the residue E146 in the catalytic process, we determined the crystal structure of the E146A mutant protein with a substrate analogue, arabinosyl-2′-fluoro- deoxy-nicotinamide adenine dinucleotide. The structure captured the enzymatic reaction intermediates in six different conformations in a crystallographic asymmetric unit. The structural results indicate a folding-back process for the adenine ring of the substrate and provide the first multiple snapshots of the process. Our approach of utilizing multiple molecules in the crystallographic asymmetric unit should be generally applicable for capturing the dynamic nature of enzymatic catalysis. © 2010 Elsevier Ltd. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/142503
ISSN
2015 Impact Factor: 4.517
2015 SCImago Journal Rankings: 3.002
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthGM061568
Research Grant Council of Hong KongHKU 765909M
HKU 769107M
N_HKU 722/08
National Science Foundation of China
Funding Information:

This work was supported, in part, by National Institutes of Health grant GM061568 (to H.C.L. and Q.H.). This work was also supported by grants HKU 765909M, HKU 769107M, and N_HKU 722/08 from the Research Grant Council of Hong Kong and the National Science Foundation of China (to Q.H., H.C.L., and L.H.Z.). The crystallographic data were collected at the Shanghai Synchrotron Radiation Facility.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorGraeff, Ren_HK
dc.contributor.authorChen, Zen_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorLee, Hen_HK
dc.contributor.authorHao, Qen_HK
dc.date.accessioned2011-10-28T02:49:26Z-
dc.date.available2011-10-28T02:49:26Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Molecular Biology, 2011, v. 405 n. 4, p. 1070-1078en_HK
dc.identifier.issn0022-2836en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142503-
dc.description.abstractThe extracellular domain of human CD38 is a multifunctional enzyme involved in the metabolism of two Ca2+ messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. When NAD is used as substrate, CD38 predominantly hydrolyzes it to ADP-ribose, with a trace amount of cyclic ADP-ribose produced through cyclization of the substrate. However, mutation of a key residue at the active site, E146, inhibits the hydrolysis activity of CD38 but greatly increases its cyclization activity. To understand the role of the residue E146 in the catalytic process, we determined the crystal structure of the E146A mutant protein with a substrate analogue, arabinosyl-2′-fluoro- deoxy-nicotinamide adenine dinucleotide. The structure captured the enzymatic reaction intermediates in six different conformations in a crystallographic asymmetric unit. The structural results indicate a folding-back process for the adenine ring of the substrate and provide the first multiple snapshots of the process. Our approach of utilizing multiple molecules in the crystallographic asymmetric unit should be generally applicable for capturing the dynamic nature of enzymatic catalysis. © 2010 Elsevier Ltd. All rights reserved.en_HK
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmben_HK
dc.relation.ispartofJournal of Molecular Biologyen_HK
dc.subjectADP-riboseen_HK
dc.subjectADPRen_HK
dc.subjectara-2′F-ADPRen_HK
dc.subjectara-2′F-NADen_HK
dc.subjectarabinosyl-2′-fluoro-deoxy-adenosine diphosphate-riboseen_HK
dc.subjectarabinosyl-2′-fluoro-deoxy-nicotinamide adenine dinucleotideen_HK
dc.subjectcADPRen_HK
dc.subjectcyclic ADP-riboseen_HK
dc.subjectPDBen_HK
dc.subjectProtein Data Banken_HK
dc.subject.meshAdenosine Diphosphate Ribose - metabolism-
dc.subject.meshAmino Acid Substitution-
dc.subject.meshAntigens, CD38 - chemistry - genetics - metabolism-
dc.subject.meshMembrane Glycoproteins - chemistry - genetics - metabolism-
dc.subject.meshNAD - metabolism-
dc.titleDynamic conformations of the CD38-mediated NAD cyclization captured in a single crystalen_HK
dc.typeArticleen_HK
dc.identifier.emailGraeff, R: graeffr@hku.hken_HK
dc.identifier.emailLee, H: leehc@hku.hken_HK
dc.identifier.emailHao, Q: qhao@hku.hken_HK
dc.identifier.authorityGraeff, R=rp01464en_HK
dc.identifier.authorityLee, H=rp00545en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.jmb.2010.11.044en_HK
dc.identifier.pmid21134381-
dc.identifier.pmcidPMC3019291-
dc.identifier.scopuseid_2-s2.0-79251593960en_HK
dc.identifier.hkuros184631en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79251593960&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume405en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1070en_HK
dc.identifier.epage1078en_HK
dc.identifier.isiWOS:000286962300013-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38-
dc.relation.projectA calcium-signaling pathway mediated by cyclic ADP-ribose and NAADP-
dc.relation.projectA new method for macromolecular structure determination: envelope-based phasing-
dc.identifier.scopusauthoridZhang, H=37035621300en_HK
dc.identifier.scopusauthoridGraeff, R=7003614053en_HK
dc.identifier.scopusauthoridChen, Z=37033573500en_HK
dc.identifier.scopusauthoridZhang, L=35744384900en_HK
dc.identifier.scopusauthoridZhang, L=35217376800en_HK
dc.identifier.scopusauthoridLee, H=26642959100en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK
dc.identifier.citeulike8362970-

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