8G9E

Crystal structure of the catalytic domain of human diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) in complex with AMP-PNP and 5-(PCF2P)-IP5, an analog of 5-IP7

Summary for 8G9E

• Entry DOI: 10.2210/pdb8g9e/pdb
• Descriptor: Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, {difluoro[(R)-hydroxy{[(1s,2R,3S,4S,5R,6S)-2,3,4,5,6-pentakis(phosphonooxy)cyclohexyl]oxy}phosphoryl]methyl}phosphonic acid, ... (5 entities in total)
• Functional Keywords: transferase inositol diphosphoinositol pentakisphosphate kinase analog methylenebisphosphonate ppip5k atp-grasp pyrophosphate diphosphate, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38970.64

Authors

Wang, H.,Shears, S.B. (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 (1.75 Å)