1K0U

Inhibition of S-adenosylhomocysteine Hydrolase by "acyclic sugar" Adenosine Analogue D-eritadenine

「1D4G」から置き換えられました

1K0U の概要

• エントリーDOI: 10.2210/pdb1k0u/pdb
• 関連するPDBエントリー: 1D4G
• 分子名称: S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, D-ERITADENINE, ... (4 entities in total)
• 機能のキーワード: s-adenosylhomocysteine, hydrolase, d-eritadenine, inhibitor
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cytoplasm: P10760
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 387058.81

構造登録者

Takusagawa, F.,Huang, Y.,Komoto, J.,Takata, Y.,Gomi, T.,Ogawa, H.,Fujioka, M.,Powell, D. (登録日: 2001-09-20, 公開日: 2001-10-17, 最終更新日: 2023-08-16)

主引用文献

Huang, Y.,Komoto, J.,Takata, Y.,Powell, D.R.,Gomi, T.,Ogawa, H.,Fujioka, M.,Takusagawa, F.
Inhibition of S-adenosylhomocysteine hydrolase by acyclic sugar adenosine analogue D-eritadenine. Crystal structure of S-adenosylhomocysteine hydrolase complexed with D-eritadenine.
J.Biol.Chem., 277:7477-7482, 2002

PubMed Abstract: D-eritadenine (DEA) is a potent inhibitor (IC(50) = 7 nm) of S-adenosyl-l-homocysteine hydrolase (AdoHcyase). Unlike cyclic sugar Ado analogue inhibitors, including mechanism-based inhibitors, DEA is an acyclic sugar Ado analogue, and the C2' and C3' have opposite chirality to those of the cyclic sugar Ado inhibitors. Crystal structures of DEA alone and in complex with AdoHcyase have been determined to elucidate the DEA binding scheme to AdoHcyase. The DEA-complexed structure has been analyzed by comparing it with two structures of AdoHcyase complexed with cyclic sugar Ado analogues. The DEA-complexed structure has a closed conformation, and the DEA is located near the bound NAD(+). However, a UV absorption measurement shows that DEA is not oxidized by the bound NAD(+), indicating that the open-closed conformational change of AdoHcyase is due to the substrate/inhibitor binding, not the oxidation state of the bound NAD. The adenine ring of DEA is recognized by four essential hydrogen bonds as observed in the cyclic sugar Ado complexes. The hydrogen bond network around the acyclic sugar moiety indicates that DEA is more tightly connected to the protein than the cyclic sugar Ado analogues. The C3'-H of DEA is pointed toward C4 of the bound NAD(+) (C3'...C4 = 3.7 A), suggesting some interaction between DEA and NAD(+). By placing DEA into the active site of the open structure, the major forces to stabilize the closed conformation of AdoHcyase are identified as the hydrogen bonds between the backbone of His-352 and the adenine ring, and the C3'-H...C4 interaction. DEA has been believed to be an inactivator of AdoHcyase, but this study indicates that DEA is a reversible inhibitor. On the basis of the complexed structure, selective inhibitors of AdoHcyase have been designed.

PubMed: 11741948
DOI: 10.1074/jbc.M109187200

実験手法

X-RAY DIFFRACTION (3 Å)