PDBsum entry: 1l1f

Oxidoreductase

PDB id: 1l1f

Contents

Protein chains

(+ 0 more) 496 a.a. *

* Residue conservation analysis

PDB id:

1l1f

Name:

Oxidoreductase

Title:

Structure of human glutamate dehydrogenase-apo form

Structure:

Glutamate dehydrogenase 1. Chain: a, b, c, d, e, f. Synonym: gdh. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Hexamer (from PQS)

Resolution:

2.70Å R-factor: 0.262 R-free: 0.302

Authors:

T.J.Smith,T.Schmidt,J.Fang,J.Wu,G.Siuzdak,C.A.Stanley

Key ref:

T.J.Smith et al. (2002). The structure of apo human glutamate dehydrogenase details subunit communication and allostery. J Mol Biol, 318, 765-777. PubMed id: 12054821 DOI: 10.1016/S0022-2836(02)00161-4

Date:

15-Feb-02 Release date: 06-Mar-02

Protein chains

P00367  (DHE3_HUMAN) -  Glutamate dehydrogenase 1, mitochondrial

Seq: 558 a.a.

Struc: 496 a.a.

Enzyme reactions

• Enzyme class: E.C.1.4.1.3 - Glutamate dehydrogenase (NAD(P)(+)).
• Reaction: L-glutamate + H₂O + NAD(P)(+) = 2-oxoglutarate + NH₃ + NAD(P)H

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: cytoplasm (3 terms)
• Biological process: metabolic process (7 terms)
• Biochemical function: catalytic activity (14 terms)

reference

DOI no: 10.1016/S0022-2836(02)00161-4

J Mol Biol 318:765-777 (2002)

PubMed id: 12054821

The structure of apo human glutamate dehydrogenase details subunit communication and allostery.

T.J.Smith, T.Schmidt, J.Fang, J.Wu, G.Siuzdak, C.A.Stanley.

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.

Selected figure(s)

Figure 1.
Figure 1. Ribbon diagram of the apo-huGDH structure. In this stereo image, the individual subunits are represented in different colors. The 3-fold axis runs vertically through the middle of the model. The antenna region is not found in bacterial or fungal GDH.

Figure 7.
Figure 7. Changes in the GTP site as the catalytic mouth opens. Shown here are three helices around the GTP binding site in the open (mauve) and closed (white) conformations. For this analysis, the two NAD binding domains are aligned according to the pivot helix. The bound GTP molecule from the boGDH·NADH·Glu·GTP complex is also shown using the same color code as the other Figures with the exception that the phosphate molecules are colored green. In this view, the antenna is on the right, and the catalytic mouth is towards the bottom. (b) A detailed view of the changes in the GTP binding site as the catalytic mouth opens. Here, the side-chains of the closed conformations colored in white and the open form side-chains are colored by atom type. The arrows denote motion as the catalytic mouth opens. The mutation sites that cause the HI/HA syndrome are denoted by asterisks. As above, the two NAD binding domains were aligned according to the pivot helix and the orientation is the same as in (a).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 318, 765-777) copyright 2002.

Figures were selected by the author.