Abstract
Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. MGST2 trimer restricts catalysis to only one out of three active sites at a time, but the molecular basis is unknown. Here, we present crystal structures of human MGST2 combined with biochemical and computational evidence for a concerted mechanism, involving local unfolding coupled to global conformational changes that regulate catalysis. Furthermore, synchronized changes in the biconical central pore modulate the hydrophobicity and control solvent influx to optimize reaction conditions at the active site. These unique mechanistic insights pertain to other, structurally related, drug targets.
Highlights
Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death
leukotriene C4 (LTC4) functions as an intracrine mediator of cell death signaled by endoplasmic reticulum stress and oxidative DNA damage induced by common chemotherapeutic agents[5]
Previous studies of MGST2 have revealed that only one out of three active sites is used at a time, an intriguing catalytic behavior observed for MGST1 and microsomal prostaglandin E synthase-1 both of which are strongly implicated in human pathophysiology[7,8,9]
Summary
Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C4, key for intracrine signaling of endoplasmic reticulum (ER) stress, oxidative DNA damage and cell death. In contrast to the holo complex, MGST2 co-crystallized with the inhibitor GSO3− reveals full occupation of all three active sites (Fig. 1c, d and Supplementary Fig. 4).
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