ADP-ribosyl cyclase: Crystal structures reveal a covalent intermediate

Michael L. Love, Doletha M.E. Szebenyi, Irina A. Kriksunov, Daniel J. Thiel, Cyrus Munshi, Richard Graeff, Hon Cheung Lee, Quan Hao

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

ADP-ribosyl cyclase catalyzes the elimination of nicotinamide from NAD and cyclization to cADPR, a known second messenger in cellular calcium signaling pathways. We have determined to 2.0 Å resolution the structure of Aplysia cyclase with ribose-5-phosphate bound covalently at C3′ and with the base exchange substrate (BES), pyridylcarbinol, bound to the active site. In addition, further refinement at 2.4 Å resolution of the structure of nicotinamide-bound cyclase, which was previously reported, reveals that ribose-5-phosphate is also covalently bound in this structure, and a second nicotinamide site was identified. The structures of native and mutant Glu179Ala cyclase were also solved to 1.7 and 2.0 Å respectively. It is proposed that the second nicotinamide site serves to promote cyclization by clearing the active site of the nicotinamide byproduct. Moreover, a ribosylation mechanism can be proposed in which the cyclization reaction proceeds through a covalently bound intermediate.

Original languageEnglish (US)
Pages (from-to)477-486
Number of pages10
JournalStructure
Volume12
Issue number3
DOIs
StatePublished - Mar 2004

Bibliographical note

Funding Information:
This work was supported by grants from the NIH to H.C.L. (GM6033) and MacCHESS (RR01646). The data were collected at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the NSF and NIH National Institute of General Medical Sciences under award DMR 9713424.

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