Structural Mechanism of Filamentation Induced Dampening of GTP Inhibition of Glutamate Dehydrogenase

Authors

Shan, Z., Darwish, N. I., Rivero-Gamez, A., Strutzenberg, T. C., Lyumkis, D., Horton, N. C.

Abstract

Glutamate dehydrogenase (GDH) is a highly regulated key enzyme that catalyzes the reversible oxidative deamination of glutamate to alpha-ketoglutarate, positioning it at a critical hub linking amino acid catabolism to energy production while supplying ammonia for urea synthesis and other nitrogen pathways. Early investigations have shown that bovine GDH (bGDH), which shares 98% sequence identity with its human homolog, assembles into polymeric filaments with altered allosteric responses. Filamentation has only relatively recently been appreciated as a widespread mechanism of enzyme regulation, prompting a reevaluation of these early observations in GDH. Here, we use high resolution cryogenic electron microscopy (cryo EM) to show that bGDH hexamers assemble via reciprocal antenna interactions that oppose the conformational changes associated with GTP inhibition, revealing how filamentation reshapes GDH allostery and with implications for the treatment of human disease.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 08 Jul 2026.

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