1WSV

Crystal Structure of Human T-protein of Glycine Cleavage System

Summary for 1WSV

• Entry DOI: 10.2210/pdb1wsv/pdb
• Related: 1WSR
• Descriptor: Aminomethyltransferase, SULFATE ION, N-[4-({[(6S)-2-AMINO-4-HYDROXY-5-METHYL-5,6,7,8-TETRAHYDROPTERIDIN-6-YL]METHYL}AMINO)BENZOYL]-L-GLUTAMIC ACID, ... (4 entities in total)
• Functional Keywords: glycine-cleavage sytem, aminomethyl transferase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion: P48728
• Total number of polymer chains: 2
• Total formula weight: 83832.04

Authors

Okamura-Ikeda, K.,Hosaka, H.,Yoshimura, M.,Yamashita, E.,Toma, S.,Nakagawa, A.,Fujiwara, K.,Motokawa, Y.,Taniguchi, H. (deposition date: 2004-11-11, release date: 2005-08-16, Last modification date: 2023-10-25)

Primary citation

Okamura-Ikeda, K.,Hosaka, H.,Yoshimura, M.,Yamashita, E.,Toma, S.,Nakagawa, A.,Fujiwara, K.,Motokawa, Y.,Taniguchi, H.
Crystal Structure of Human T-protein of Glycine Cleavage System at 2.0A Resolution and its Implication for Understanding Non-ketotic Hyperglycinemia
J.Mol.Biol., 351:1146-1159, 2005

PubMed Abstract: T-protein, a component of the glycine cleavage system, catalyzes the formation of ammonia and 5,10-methylenetetrahydrofolate from the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein. Several mutations in the human T-protein gene cause non-ketotic hyperglycinemia. To gain insights into the effect of disease-causing mutations and the catalytic mechanism at the molecular level, crystal structures of human T-protein in free form and that bound to 5-methyltetrahydrofolate (5-CH3-H4folate) have been determined at 2.0 A and 2.6 A resolution, respectively. The overall structure consists of three domains arranged in a cloverleaf-like structure with the central cavity, where 5-CH3-H4folate is bound in a kinked shape with the pteridine group deeply buried into the hydrophobic pocket and the glutamyl group pointed to the C-terminal side surface. Most of the disease-related residues cluster around the cavity, forming extensive hydrogen bonding networks. These hydrogen bonding networks are employed in holding not only the folate-binding space but also the positions and the orientations of alpha-helix G and the following loop in the middle region, which seems to play a pivotal role in the T-protein catalysis. Structural and mutational analyses demonstrated that Arg292 interacts through water molecules with the folate polyglutamate tail, and that the invariant Asp101, located close to the N10 group of 5-CH3-H4folate, might play a key role in the initiation of the catalysis by increasing the nucleophilic character of the N10 atom of the folate substrate for the nucleophilic attack on the aminomethyl lipoate intermediate. A clever mechanism of recruiting the aminomethyl lipoate arm to the reaction site seems to function as a way of avoiding the release of toxic formaldehyde.

PubMed: 16051266
DOI: 10.1016/j.jmb.2005.06.056

Experimental method

X-RAY DIFFRACTION (2.6 Å)