4NZN

Crystal structure of the catalytic domain of PPIP5K2 in complex with AMPPNP and 2-O-BN-5-PA-INSP4

Summary for 4NZN

• Entry DOI: 10.2210/pdb4nzn/pdb
• Related: 3T9B 4NZM 4NZO
• Descriptor: Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, (2-{[(1s,2R,3R,4r,5S,6S)-4-(benzyloxy)-2,3,5,6-tetrakis(phosphonooxy)cyclohexyl]oxy}-2-oxoethyl)phosphonic acid, ... (5 entities in total)
• Functional Keywords: atp-grasp fold, inositol pyrophosphate kinase, drug discovery, kinase, enzymology, inositol pyrophosphates, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytosol: O43314
• Total number of polymer chains: 1
• Total formula weight: 38860.22

Authors

Wang, H.,Shears, S.B. (deposition date: 2013-12-12, release date: 2014-04-02, Last modification date: 2023-09-20)

Primary citation

Wang, H.,Godage, H.Y.,Riley, A.M.,Weaver, J.D.,Shears, S.B.,Potter, B.V.
Synthetic Inositol Phosphate Analogs Reveal that PPIP5K2 Has a Surface-Mounted Substrate Capture Site that Is a Target for Drug Discovery.
Chem.Biol., 21:689-699, 2014

PubMed Abstract: Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP-InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design.

PubMed: 24768307
DOI: 10.1016/j.chembiol.2014.03.009

Experimental method

X-RAY DIFFRACTION (1.75 Å)