Crystal structure of human diphosphoinositol phosphatase 1

Thorsell, A.G.; Persson, C.; Gräslund, S.; Hammarstrom, M.; Busam, R.D.; Hällberg, B. Martin

doi:10.1002/prot.22489

Cited by 26 publications

(39 citation statements)

References 23 publications

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“…Finally, the most remarkable MFx structure is that of a human diphosphoinositol phosphatase, co-crystalized with myo-inositol hexakis-phosphate and then soaked with sodium fluoride (PDB: 2q9p). [33] The resulting complex has four octahedral magnesiums with nine ligands assigned as fluorines. This complex embraces MgF2, MgF3, MgF4, and MgF5 species in a single complex and offers the first example of octahedral MgFx (Fig.…”

Section: Aluminum Trifluoride Alf3mentioning

confidence: 99%

Metal Fluorides as Analogues for Studies on Phosphoryl Transfer Enzymes

et al. 2017

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Abstract:The 1994 structure of a transition state analog with AlF4 -and GDP complexed to G1α, a small G protein, heralded a new field of research into structure and mechanism of enzymes that manipulate transfer of the phosphoryl (PO3 -) group. The list of enzyme structures that embrace metal fluorides, MFx, as ligands that imitate either the phosphoryl group or a phosphate, is now growing at over 80 per triennium. They fall into three distinct geometrical classes: (i) Tetrahedral complexes, based on BeF3 -, mimic ground state phosphates; (ii) Octahedral complexes, primarily based on AlF4 -, mimic "in-line" anionic transition state for phosphoryl transfer; and (iii) Trigonal bipyramidal complexes, represented by MgF3 -and putative AlF3 0 moieties, additionally mimic the tbp geometry of the transition state. The interpretation of these structures provides a deeper mechanistic understanding of the behavior and manipulation of phosphate monoesters in molecular biology. This review provides a comprehensive overview of these structures, their uses, and their computational development. It questions the identification of AlF3 0 and MgF4 = as tbp species in protein complexes and discusses the relevance of physical organic chemistry and water-based model studies for understanding phosphoryl group transfer in enzymes. It describes two roles for amino acid side-chains that mediate proton transfers during phosphoryl transfer, based on the analysis of protein/MFx structures. First, they deploy hydrogen bonding to neutral oxygen nucleophiles so as to orientate them for correct orbital overlap with the electrophilic phosphorus center. Secondly, they behave as classical general acid/base catalysts.

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Section: Aluminum Trifluoride Alf3mentioning

confidence: 99%

Metal Fluorides as Analogues for Studies on Phosphoryl Transfer Enzymes

et al. 2017

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“…A detailed mutagenic study has revealed that the specificity of human DIPP1 towards diphosphoinositol polyphosphates is entrusted to several amino acid residues that lie outside the Nudix motif (Yang et al, 1999). The structures of several Nudix proteins have been solved, but to date only one DIPP structure has been published (human DIPP1; (Thorsell et al, 2009)).…”

Section: The Structure Of a Dippmentioning

confidence: 99%

Structural insight into inositol pyrophosphate turnover

Shears

Weaver

Wang

2013

Advances in Biological Regulation

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The diphosphoinositol polyphosphates (“inositol pyrophosphates”; PP-InsPs) regulate many cellular processes in eukaryotes, including stress responses, apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, telomere maintenance, insulin signaling and neutrophil activation. Thus, the enzymes that control the metabolism of the PP-InsPs serve important cell signaling roles. In order to fully characterize how these enzymes are regulated, we need to determine the atomic-level architecture of their active sites. Only then can we fully appreciate reaction mechanisms and their modes of regulation. In this review, we summarize published information obtained from the structural analysis of a human diphosphoinositol polyphosphate phosphohydrolase (DIPP), and a human diphosphoinositol polyphosphate kinase (PPIP5K). This work includes the analysis of crystal complexes with substrates, products, transition state analogues, and a novel phosphonoacetate substrate analogue.

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“…That is, 1-PP-InsP 5 and 3-PP-InsP 5 are an enantiomeric pair, and a stereoselective technique is needed in order to distinguish between them. A recent molecular modeling study tentatively proposed that the Vip1/PPIP5Ks are 3-kinases (Thorsell et al, 2009); on the contrary, some unpublished data that were cited in a recent review (Best et al, 2010) suggest a 1-kinase specificity. The placement of this diphosphate at the 1-position in Fig.…”

Section: Metabolism Of the Diphosphoinositol Polyphosphatesmentioning

confidence: 99%