8T99

Diphosphoinositol polyphosphate phosphohydrolase 1 (DIPP1/NUDT3) in complex with Scyllo-L-1,4-[PP]2-(2,3)IP2, Mg, and Fluoride ion

Summary for 8T99

• Entry DOI: 10.2210/pdb8t99/pdb
• Descriptor: Diphosphoinositol polyphosphate phosphohydrolase 1, (1R,2S,3S,4R,5S,6S)-2,3-dihydroxy-5,6-bis(phosphonooxy)cyclohexane-1,4-diyl bis[trihydrogen (diphosphate)], MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: inositol phosphate, inositol, phosphatase, nut3, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17938.22

Authors

Zong, G.,Wang, H.,Shears, S.B. (deposition date: 2023-06-23, release date: 2023-11-15, Last modification date: 2024-02-14)

Primary citation

Zong, G.,Desfougeres, Y.,Portela-Torres, P.,Kwon, Y.U.,Saiardi, A.,Shears, S.B.,Wang, H.
Biochemical and structural characterization of an inositol pyrophosphate kinase from a giant virus.
Embo J., 43:462-480, 2024

PubMed Abstract: Kinases that synthesize inositol phosphates (IPs) and pyrophosphates (PP-IPs) control numerous biological processes in eukaryotic cells. Herein, we extend this cellular signaling repertoire to viruses. We have biochemically and structurally characterized a minimalist inositol phosphate kinase (i.e., TvIPK) encoded by Terrestrivirus, a nucleocytoplasmic large ("giant") DNA virus (NCLDV). We show that TvIPK can synthesize inositol pyrophosphates from a range of scyllo- and myo-IPs, both in vitro and when expressed in yeast cells. We present multiple crystal structures of enzyme/substrate/nucleotide complexes with individual resolutions from 1.95 to 2.6 Å. We find a heart-shaped ligand binding pocket comprising an array of positively charged and flexible side chains, underlying the observed substrate diversity. A crucial arginine residue in a conserved "G-loop" orients the γ-phosphate of ATP to allow substrate pyrophosphorylation. We highlight additional conserved catalytic and architectural features in TvIPK, and support their importance through site-directed mutagenesis. We propose that NCLDV inositol phosphate kinases may have assisted evolution of inositol pyrophosphate signaling, and we discuss the potential biogeochemical significance of TvIPK in soil niches.

PubMed: 38216735
DOI: 10.1038/s44318-023-00005-0

Experimental method

X-RAY DIFFRACTION (1.5 Å)