1MC5

Ternary complex of Human glutathione-dependent formaldehyde dehydrogenase with S-(hydroxymethyl)glutathione and NADH

Summary for 1MC5

• Entry DOI: 10.2210/pdb1mc5/pdb
• Descriptor: Alcohol dehydrogenase class III chi chain, ZINC ION, POTASSIUM ION, ... (7 entities in total)
• Functional Keywords: glutathione-dependent formaldehyde dehydrogenase, class iii alcohol dehydrogenase, s-(hydroxymethyl)glutathione, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P11766
• Total number of polymer chains: 2
• Total formula weight: 81794.23

Authors

Sanghani, P.C.,Bosron, W.F.,Hurley, T.D. (deposition date: 2002-08-05, release date: 2003-03-04, Last modification date: 2024-02-14)

Primary citation

Sanghani, P.C.,Bosron, W.F.,Hurley, T.D.
Human glutathione-dependent formaldehyde dehydrogenase. Structural changes associated with Ternary Complex formation
Biochemistry, 41:15189-15194, 2002

PubMed Abstract: Human glutathione-dependent formaldehyde dehydrogenase plays an important role in the metabolism of glutathione adducts such as S-(hydroxymethyl)glutathione and S-nitrosoglutathione. The role of specific active site residues in binding these physiologically important substrates and the structural changes during the catalytic cycle of glutathione-dependent formaldehyde dehydrogenase was examined by determining the crystal structure of a ternary complex with S-(hydroxymethyl)glutathione and the reduced coenzyme to 2.6 A resolution. The formation of the ternary complex caused the movement of the catalytic domain toward the coenzyme-binding domain. This represents the first observation of domain closure in glutathione-dependent formaldehyde dehydrogenase in response to substrate binding. A water molecule adjacent to the 2'-ribose hydroxyl of NADH suggests that the alcohol proton is relayed to solvent directly from the coenzyme, rather than through the action of the terminal histidine residue as observed in the proton relay system for class I alcohol dehydrogenases. S-(Hydroxymethyl)glutathione is directly coordinated to the active site zinc and forms interactions with the highly conserved residues Arg114, Asp55, Glu57, and Thr46. The active site zinc has a tetrahedral coordination environment with Cys44, His66, and Cys173 as the three protein ligands in addition to S-(hydroxymethyl)glutathione. This is in contrast to zinc coordination in the binary coenzyme complex where all of the ligands were contributed by the enzyme and included Glu67 as the fourth protein ligand. This change in zinc coordination is accomplished by an approximately 2.3 A movement of the catalytic zinc.

PubMed: 12484756
DOI: 10.1021/bi026705q

Experimental method

X-RAY DIFFRACTION (2.6 Å)