6WOI
Diphosphoinositol polyphosphate phosphohydrolase 1 (DIPP1/NUDT3) in complex with 1-Diphosphoinositol pentakisphosphate, Mg, and Fluoride ion, presoaked with 1,5-IP8, Mg and Fluoride for 30 seconds
Summary for 6WOI
| Entry DOI | 10.2210/pdb6woi/pdb |
| Descriptor | Diphosphoinositol polyphosphate phosphohydrolase 1, (1S,2R,3R,4S,5S,6R)-2,3,4,5,6-pentakis(phosphonooxy)cyclohexyl trihydrogen diphosphate, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | phosphatase, nudix, catalysis mechanism, substrate specificity, inositol, inositol pyrophosphate, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20445.76 |
| Authors | Zong, G.N.,Wang, H.C.,Shears, S.B. (deposition date: 2020-04-24, release date: 2021-03-03, Last modification date: 2024-03-06) |
| Primary citation | Zong, G.,Jork, N.,Hostachy, S.,Fiedler, D.,Jessen, H.J.,Shears, S.B.,Wang, H. New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1. Faseb J., 35:e21275-e21275, 2021 Cited by PubMed Abstract: Nudix hydrolases attract considerable attention for their wide range of specialized activities in all domains of life. One particular group of Nudix phosphohydrolases (DIPPs), through their metabolism of diphosphoinositol polyphosphates (PP-InsPs), regulates the actions of these polyphosphates upon bioenergetic homeostasis. In the current study, we describe, at an atomic level, hitherto unknown properties of human DIPP1.We provide X-ray analysis of the catalytic core of DIPP1 in crystals complexed with either natural PP-InsPs, alternative PP-InsP stereoisomers, or non-hydrolysable methylene bisphosphonate analogs ("PCP-InsPs"). The conclusions that we draw from these data are interrogated by studying the impact upon catalytic activity upon mutagenesis of certain key residues. We present a picture of a V-shaped catalytic furrow with overhanging ridges constructed from flexible positively charged side chains; within this cavity, the labile phosphoanhydride bond is appropriately positioned at the catalytic site by an extensive series of interlocking polar contacts which we analogize as "suspension cables." We demonstrate functionality for a triglycine peptide within a β-strand which represents a non-canonical addition to the standard Nudix catalytic core structure. We describe pre-reaction enzyme/substrate states which we posit to reflect a role for electrostatic steering in substrate capture. Finally, through time-resolved analysis, we uncover a chronological sequence of DIPP1/product post-reaction states, one of which may rationalize a role for InsP as an inhibitor of catalytic activity. PubMed: 33475202DOI: 10.1096/fj.202001489R PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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