8G9C

Diphosphoinositol polyphosphate phosphohydrolase 1 (DIPP1/NUDT3) in complex with 5- difluoromethylenebisphosphonate inositol pentakisphosphate (5-PCF2P-IP5), an analogue of 5-InsP7

Summary for 8G9C

• Entry DOI: 10.2210/pdb8g9c/pdb
• Descriptor: Diphosphoinositol polyphosphate phosphohydrolase 1, {difluoro[(R)-hydroxy{[(1s,2R,3S,4S,5R,6S)-2,3,4,5,6-pentakis(phosphonooxy)cyclohexyl]oxy}phosphoryl]methyl}phosphonic acid, 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: 20458.12

Authors

Zong, G.,Wang, H.,Shears, S. (deposition date: 2023-02-21, release date: 2024-01-03)

Primary citation

Hostachy, S.,Wang, H.,Zong, G.,Franke, K.,Riley, A.M.,Schmieder, P.,Potter, B.V.L.,Shears, S.B.,Fiedler, D.
Fluorination Influences the Bioisostery of Myo-Inositol Pyrophosphate Analogs.
Chemistry, 29:e202302426-e202302426, 2023

PubMed Abstract: Inositol pyrophosphates (PP-IPs) are densely phosphorylated messenger molecules involved in numerous biological processes. PP-IPs contain one or two pyrophosphate group(s) attached to a phosphorylated myo-inositol ring. 5PP-IP is the most abundant PP-IP in human cells. To investigate the function and regulation by PP-IPs in biological contexts, metabolically stable analogs have been developed. Here, we report the synthesis of a new fluorinated phosphoramidite reagent and its application for the synthesis of a difluoromethylene bisphosphonate analog of 5PP-IP . Subsequently, the properties of all currently reported analogs were benchmarked using a number of biophysical and biochemical methods, including co-crystallization, ITC, kinase activity assays and chromatography. Together, the results showcase how small structural alterations of the analogs can have notable effects on their properties in a biochemical setting and will guide in the choice of the most suitable analog(s) for future investigations.

PubMed: 37773020
DOI: 10.1002/chem.202302426

Experimental method

X-RAY DIFFRACTION (1.4 Å)