3ETG

Glutamate dehydrogenase complexed with GW5074

Summary for 3ETG

• Entry DOI: 10.2210/pdb3etg/pdb
• Related: 3ETD 3ETE
• Descriptor: Glutamate dehydrogenase, GLUTAMIC ACID, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: glutamate dehydrogenase, gw5074, inhibition, oxidoreductase
• Biological source: Bos taurus
• Total number of polymer chains: 6
• Total formula weight: 345911.27

Authors

Li, M.,Smith, T.J. (deposition date: 2008-10-07, release date: 2009-06-09, Last modification date: 2023-12-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)