Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis

• Published in: Nature communications Vol. 12; no. 1; pp. 1728 - 12
• Main Authors: Thulasingam, Madhuranayaki, Orellana, Laura, Nji, Emmanuel, Ahmad, Shabbir, Rinaldo-Matthis, Agnes, Haeggström, Jesper Z
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.03.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Apoptosis; Binding Sites; Catalysis; Catalytic Domain; Cell death; Computer applications; Crystal structure; Crystallography, X-Ray; DNA damage; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Glutathione; Glutathione transferase; Glutathione Transferase - chemistry; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Humans; Hydrophobicity; Leukotriene C4 - metabolism; Medicin och hälsovetenskap; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Oxidative Stress; Protein Conformation; Therapeutic targets; Trimers
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21924-8

Microsomal glutathione S-transferase 2 (MGST2) produces leukotriene C , 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.