3ETD

Structure of glutamate dehydrogenase complexed with bithionol

3ETD の概要

• エントリーDOI: 10.2210/pdb3etd/pdb
• 関連するPDBエントリー: 3ETE 3ETG
• 分子名称: GLUD1 protein, GLUTAMIC ACID, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• 機能のキーワード: glutamate dehydrogenase, inhibitors, bithionol, oxidoreductase
• 由来する生物種: Bos taurus (bovine,cow)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 344921.93

構造登録者

Li, M.,Smith, T.J. (登録日: 2008-10-07, 公開日: 2009-06-09, 最終更新日: 2023-12-27)

主引用文献

Li, M.,Smith, C.J.,Walker, M.T.,Smith, T.J.
Novel Inhibitors Complexed with Glutamate Dehydrogenase: ALLOSTERIC REGULATION BY CONTROL OF PROTEIN DYNAMICS
J.Biol.Chem., 284:22988-23000, 2009

PubMed Abstract: Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH.

PubMed: 19531491
DOI: 10.1074/jbc.M109.020222

実験手法

X-RAY DIFFRACTION (2.5 Å)