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Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation

Author

Listed:
  • Lionel Ballut

    (BioCrystallography and Structural Biology of Therapeutic Targets Group, Molecular and Structural Bases of Infectious Systems, UMR5086 CNRS-University of Lyon 1, 7 passage du Vercors)

  • Sébastien Violot

    (BioCrystallography and Structural Biology of Therapeutic Targets Group, Molecular and Structural Bases of Infectious Systems, UMR5086 CNRS-University of Lyon 1, 7 passage du Vercors)

  • Santosh Shivakumaraswamy

    (Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research)

  • Lakshmi Prasoona Thota

    (Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research)

  • Manu Sathya

    (Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research)

  • Jyothirmai Kunala

    (Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research)

  • Bauke W. Dijkstra

    (Laboratory of Biophysical Chemistry, University of Groningen)

  • Raphaël Terreux

    (Bioinformatics: Structures and Interactions Group, Molecular and Structural Bases of Infectious Systems, UMR5086 CNRS-University of Lyon 1)

  • Richard Haser

    (BioCrystallography and Structural Biology of Therapeutic Targets Group, Molecular and Structural Bases of Infectious Systems, UMR5086 CNRS-University of Lyon 1, 7 passage du Vercors)

  • Hemalatha Balaram

    (Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research)

  • Nushin Aghajari

    (BioCrystallography and Structural Biology of Therapeutic Targets Group, Molecular and Structural Bases of Infectious Systems, UMR5086 CNRS-University of Lyon 1, 7 passage du Vercors)

Abstract

GMP synthetase (GMPS), a key enzyme in the purine biosynthetic pathway performs catalysis through a coordinated process across two catalytic pockets for which the mechanism remains unclear. Crystal structures of Plasmodium falciparum GMPS in conjunction with mutational and enzyme kinetic studies reported here provide evidence that an 85° rotation of the GATase domain is required for ammonia channelling and thus for the catalytic activity of this two-domain enzyme. We suggest that conformational changes in helix 371–375 holding catalytic residues and in loop 376–401 along the rotation trajectory trigger the different steps of catalysis, and establish the central role of Glu374 in allostery and inter-domain crosstalk. These studies reveal the mechanism of domain rotation and inter-domain communication, providing a molecular framework for the function of all single polypeptide GMPSs and form a solid basis for rational drug design targeting this therapeutically important enzyme.

Suggested Citation

  • Lionel Ballut & Sébastien Violot & Santosh Shivakumaraswamy & Lakshmi Prasoona Thota & Manu Sathya & Jyothirmai Kunala & Bauke W. Dijkstra & Raphaël Terreux & Richard Haser & Hemalatha Balaram & Nushi, 2015. "Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9930
    DOI: 10.1038/ncomms9930
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    Cited by:

    1. Sourav Ghosh & Rajib Kundu & Manjunatha Chandana & Rahul Das & Aditya Anand & Subhashree Beura & Ruchir Chandrakant Bobde & Vishal Jain & Sowmya Ramakant Prabhu & Prativa Kumari Behera & Akshaya Kumar, 2023. "Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement," Nature Communications, Nature, vol. 14(1), pages 1-27, December.

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