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Article: Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog

TitleCatalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog
Authors
Issue Date2007
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2007, v. 282 n. 34, p. 24825-24832 How to Cite?
AbstractCyclic 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 IC50 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 Å resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 Å) 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. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/91905
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Qen_HK
dc.contributor.authorKriksunov, IAen_HK
dc.contributor.authorMoreau, Cen_HK
dc.contributor.authorGraeff, Ren_HK
dc.contributor.authorPotter, BVLen_HK
dc.contributor.authorHon, CLen_HK
dc.contributor.authorHao, Qen_HK
dc.date.accessioned2010-09-17T10:30:07Z-
dc.date.available2010-09-17T10:30:07Z-
dc.date.issued2007en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2007, v. 282 n. 34, p. 24825-24832en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91905-
dc.description.abstractCyclic 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 IC50 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 Å resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 Å) 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. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.titleCatalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analogen_HK
dc.typeArticleen_HK
dc.identifier.emailGraeff, R: graeffr@hku.hken_HK
dc.identifier.emailHon, CL: leehc@hku.hken_HK
dc.identifier.emailHao, Q: qhao@hku.hken_HK
dc.identifier.authorityGraeff, R=rp01464en_HK
dc.identifier.authorityHon, CL=rp00545en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.M701653200en_HK
dc.identifier.pmid17591784-
dc.identifier.scopuseid_2-s2.0-34548317513en_HK
dc.identifier.hkuros140344-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34548317513&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume282en_HK
dc.identifier.issue34en_HK
dc.identifier.spage24825en_HK
dc.identifier.epage24832en_HK
dc.identifier.eissn1083-351Xen_US
dc.identifier.isiWOS:000248933000038-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLiu, Q=35215401600en_HK
dc.identifier.scopusauthoridKriksunov, IA=6507909504en_HK
dc.identifier.scopusauthoridMoreau, C=7103276407en_HK
dc.identifier.scopusauthoridGraeff, R=7003614053en_HK
dc.identifier.scopusauthoridPotter, BVL=16073310200en_HK
dc.identifier.scopusauthoridHon, CL=26642959100en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK

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