1q33
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Crystal structure of human ADP-ribose pyrophosphatase NUDT9
OverviewOverview
Human ADP-ribose pyrophosphatase NUDT9 belongs to a superfamily of Nudix, hydrolases that catabolize potentially toxic compounds in the cell. The, enzyme hydrolyzes ADP-ribose (ADPR) to AMP and ribose 5'-phosphate. NUDT9, shares 39% sequence identity with the C-terminal cytoplasmic domain of the, ADPR-gated calcium channel TRPM2, which exhibits low but specific enzyme, activity. We determined crystal structures of NUDT9 in the presence and in, the absence of the reaction product ribose 5'-phosphate. On the basis of, these structures and comparison with a bacterial homologue, a model of the, substrate complex was built. The structure and activity of a double point, mutant (R(229)E(230)F(231) to R(229)I(230)L(231)), which mimics the Nudix, signature of the ion channel domain, was determined. Finally, the, activities of a pair of additional mutated constructs were compared to the, wild-type enzyme. The first corresponds to a minimal Nudix domain missing, an N-terminal domain and C-terminal tail; the second disrupts two, potential general bases in the active site. NUDT9 contains an N-terminal, domain with a novel fold and a catalytic C-terminal Nudix domain. Unlike, its closest functional homologue (homodimeric Escherichia coli ADPRase), it is active as a monomer, and the substrate is bound in a cleft between, the domains. The structure of the RIL mutant provides structural basis for, the reduced activity of the TRPM2 ion channel. The conformation and, binding interactions of ADPR substrate are predicted to differ from those, observed for E.coli ADPRase; mutation of structurally aligned acidic, residues in their active sites produce significantly different effects on, catalytic efficiency, indicating that their reaction pathways and, mechanisms may have diverged.
About this StructureAbout this Structure
1Q33 is a Single protein structure of sequence from Homo sapiens with GLC and SO4 as ligands. Active as ADP-ribose diphosphatase, with EC number 3.6.1.13 Full crystallographic information is available from OCA.
ReferenceReference
The crystal structure and mutational analysis of human NUDT9., Shen BW, Perraud AL, Scharenberg A, Stoddard BL, J Mol Biol. 2003 Sep 12;332(2):385-98. PMID:12948489
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