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Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis

Author

Listed:
  • Madhuranayaki Thulasingam

    (Karolinska Institutet)

  • Laura Orellana

    (Stockholm University
    Karolinska Institutet)

  • Emmanuel Nji

    (Stockholm University
    BioStruct-Africa)

  • Shabbir Ahmad

    (Karolinska Institutet
    Uppsala University)

  • Agnes Rinaldo-Matthis

    (Karolinska Institutet)

  • Jesper Z. Haeggström

    (Karolinska Institutet)

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.

Suggested Citation

  • Madhuranayaki Thulasingam & Laura Orellana & Emmanuel Nji & Shabbir Ahmad & Agnes Rinaldo-Matthis & Jesper Z. Haeggström, 2021. "Crystal structures of human MGST2 reveal synchronized conformational changes regulating catalysis," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21924-8
    DOI: 10.1038/s41467-021-21924-8
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