NIH Research Festival
Dysregulation of glutamate dehydrogenase (GDH), an enzyme that catalyzes the oxydative deamination of glutamate, leads to a variety of metabolic and neurological disorders. Here, we report near-atomic resolution cryo-EM structures for five GDH complexes for which crystal structures are not yet available. We show that the binding of the metabolite NADH to the catalytic site results in an equilibrium in which each of the protomers in the hexameric enzyme complex is in either an all-open or all-closed conformation. NADH is also bound at a regulatory site in each protomer, but in contrast to binding at the catalytic site, the orientation of bound NADH differs between closed and open conformations. Critically, we find that NADH and GTP binding are each important factors that stabilize the closed conformation, but that NADH binding alone is necessary and sufficient to allow the transition between open and closed conformations.
Scientific Focus Area: Structural Biology
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