4NZO

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

4NZO の概要

• エントリーDOI: 10.2210/pdb4nzo/pdb
• 関連するPDBエントリー: 3T9B 4NZM 4NZN
• 分子名称: Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 2, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, (1R,2R,3r,4S,5S,6s)-3,6-bis(benzyloxy)cyclohexane-1,2,4,5-tetrayl tetrakis[dihydrogen (phosphate)], ... (5 entities in total)
• 機能のキーワード: atp-grasp fold, inositol pyrophosphate kinase, kinase, drug discovery, enzymology, inositol pyrophosphates, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytosol: O43314
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38828.32

構造登録者

Wang, H.,Shears, S.B. (登録日: 2013-12-12, 公開日: 2014-04-02, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.9 Å)