Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis

Area of Science:

• Biochemistry
• Structural Biology
• Cellular Biology

Background:

• Microsomal glutathione S-transferase 2 (MGST2) is crucial for leukotriene C4 production, mediating endoplasmic reticulum (ER) stress, oxidative DNA damage, and cell death.
• The MGST2 trimer exhibits restricted catalytic activity, with only one active site functional at a time, but the underlying molecular mechanism remains unelucidated.

Purpose of the Study:

• To elucidate the molecular basis for the restricted catalytic activity of the MGST2 trimer.
• To understand the concerted mechanism regulating MGST2 catalysis and its impact on cellular processes.

Main Methods:

• X-ray crystallography of human MGST2.
• Biochemical assays to assess enzyme activity.
• Computational modeling to investigate reaction mechanisms.

Main Results:

• Crystal structures reveal a concerted mechanism involving local unfolding and global conformational changes in MGST2.
• Synchronized alterations in the central pore modulate hydrophobicity and solvent access to the active site.
• These structural dynamics optimize reaction conditions for MGST2 catalysis.

Conclusions:

• MGST2 employs a unique, coordinated mechanism to regulate its catalytic activity, involving dynamic structural rearrangements.
• Understanding this mechanism provides insights into ER stress, oxidative damage, and cell death pathways.
• The findings have implications for drug discovery targeting structurally related enzymes.