3I9M

Crystal structure of human CD38 complexed with an analog ara-2'F-ADPR

Summary for 3I9M

• Entry DOI: 10.2210/pdb3i9m/pdb
• Related: 3I9J 3I9K 3I9L 3I9N
• Descriptor: ADP-ribosyl cyclase 1, [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl [(2R,3R,4R)-4-fluoro-3-hydroxytetrahydrofuran-2-yl]methyl dihydrogen diphosphate (3 entities in total)
• Functional Keywords: enzyme-analog complex, covalent reaction intermediate, alpha helices rich domain and alpha/beta domain, alternative splicing, diabetes mellitus, disulfide bond, glycoprotein, hydrolase, membrane, nad, polymorphism, receptor, signal-anchor, transmembrane
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type II membrane protein: P28907
• Total number of polymer chains: 2
• Total formula weight: 61851.40

Authors

Liu, Q.,Graeff, R.,Kriksunov, I.A.,Jiang, H.,Zhang, B.,Oppenheimer, N.,Lin, H.,Potter, B.V.L.,Lee, H.C.,Hao, Q. (deposition date: 2009-07-12, release date: 2009-07-28, Last modification date: 2023-11-01)

Primary citation

Liu, Q.,Graeff, R.,Kriksunov, I.A.,Jiang, H.,Zhang, B.,Oppenheimer, N.,Lin, H.,Potter, B.V.L.,Lee, H.C.,Hao, Q.
Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase
J.Biol.Chem., 284:27637-27645, 2009

PubMed Abstract: Cyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulates many physiological processes. The production and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-ribosyl cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38 structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation of Phe-174 to glycine can turn ADPRC from a cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a cyclase to a hydrolase.

PubMed: 19640846
DOI: 10.1074/jbc.M109.031005

Experimental method

X-RAY DIFFRACTION (1.75 Å)