The ligand-induced structural changes of human L-Arginine:Glycine amidinotransferase. A mutational and crystallographic study.

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Fritsche E, Humm A, Huber R

The ligand-induced structural changes of human L-Arginine:Glycine amidinotransferase. A mutational and crystallographic study.

J Biol Chem. 1999 Jan 29;274(5):3026-32.

PubMed ID

9915841 [ View in PubMed

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Abstract

Human L-arginine:glycine amidinotransferase (AT) shows large structural changes of the 300-flap and of helix H9 upon binding of L-arginine and L-ornithine, described as a closed and an open conformation (Humm, A., Fritsche, E., Steinbacher, S., and Huber, R. (1997) EMBO J. 16, 3373-3385). To elucidate the structural basis of these induced-fit movements, the x-ray structures of AT in complex with the amidino acceptor glycine and its analogs gamma-aminobutyric acid and delta-aminovaleric acid, as well as in complex with the amidino donor analogs L-alanine, L-alpha-aminobutyric acid, and L-norvaline, have been solved at 2.6-, 2.5-, 2.37-, 2.3-, 2.5-, and 2.4-A resolutions, respectively. The latter three compounds were found to stabilize the open conformer. The glycine analogs bind in a distinct manner and do not induce the transition to the open state. The complex with glycine revealed a third binding mode, reflecting the rather broad substrate specificity of AT. These findings identified a role for the alpha-amino group of the ligand in stabilizing the open conformer. The kinetic, structural, and thermodynamic properties of the mutants ATDeltaM302 and ATDelta11 (lacks 11 residues of H9) confirmed the key role of Asn300 and suggest that in mammalian amidinotransferases, the role of helix H9 is in accelerating amidino transfer by an induced-fit mechanism. Helix H9 does not add to the stability of the protein.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
gamma-Aminobutyric acid	Glycine amidinotransferase, mitochondrial	Protein	Humans	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
Glycine amidinotransferase, mitochondrial	P50440	Details