1L1F

Structure of human glutamate dehydrogenase-apo form

Summary for 1L1F

• Entry DOI: 10.2210/pdb1l1f/pdb
• Related: 1HWX 1HWY 1HWZ
• Descriptor: Glutamate Dehydrogenase 1 (1 entity in total)
• Functional Keywords: allostery, negative cooperativity, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion matrix: P00367
• Total number of polymer chains: 6
• Total formula weight: 336513.40

Authors

Smith, T.J.,Schmidt, T.,Fang, J.,Wu, J.,Siuzdak, G.,Stanley, C.A. (deposition date: 2002-02-15, release date: 2002-03-06, Last modification date: 2024-02-14)

Primary citation

Smith, T.J.,Schmidt, T.,Fang, J.,Wu, J.,Siuzdak, G.,Stanley, C.A.
The structure of apo human glutamate dehydrogenase details subunit communication and allostery.
J.Mol.Biol., 318:765-777, 2002

PubMed Abstract: The structure of human glutamate dehydrogenase (GDH) has been determined in the absence of active site and regulatory ligands. Compared to the structures of bovine GDH that were complexed with coenzyme and substrate, the NAD binding domain is rotated away from the glutamate-binding domain. The electron density of this domain is more disordered the further it is from the pivot helix. Mass spectrometry results suggest that this is likely due to the apo form being more dynamic than the closed form. The antenna undergoes significant conformational changes as the catalytic cleft opens. The ascending helix in the antenna moves in a clockwise manner and the helix in the descending strand contracts in a manner akin to the relaxation of an extended spring. A number of spontaneous mutations in this antenna region cause the hyperinsulinism/hyperammonemia syndrome by decreasing GDH sensitivity to the inhibitor, GTP. Since these residues do not directly contact the bound GTP, the conformational changes in the antenna are apparently crucial to GTP inhibition. In the open conformation, the GTP binding site is distorted such that it can no longer bind GTP. In contrast, ADP binding benefits by the opening of the catalytic cleft since R463 on the pivot helix is pushed into contact distance with the beta-phosphate of ADP. These results support the previous proposal that purines regulate GDH activity by altering the dynamics of the NAD binding domain. Finally, a possible structural mechanism for negative cooperativity is presented.

PubMed: 12054821
DOI: 10.1016/S0022-2836(02)00161-4

Experimental method

X-RAY DIFFRACTION (2.7 Å)