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Structure of the class D GPCR Ste2 dimer coupled to two G proteins

Author

Listed:
  • Vaithish Velazhahan

    (MRC Laboratory of Molecular Biology)

  • Ning Ma

    (Beckman Research Institute of the City of Hope)

  • Gáspár Pándy-Szekeres

    (Universitetsparken 2
    Research Center for Natural Sciences)

  • Albert J. Kooistra

    (Universitetsparken 2)

  • Yang Lee

    (MRC Laboratory of Molecular Biology)

  • David E. Gloriam

    (Universitetsparken 2)

  • Nagarajan Vaidehi

    (Beckman Research Institute of the City of Hope)

  • Christopher G. Tate

    (MRC Laboratory of Molecular Biology)

Abstract

G-protein-coupled receptors (GPCRs) are divided phylogenetically into six classes1,2, denoted A to F. More than 370 structures of vertebrate GPCRs (belonging to classes A, B, C and F) have been determined, leading to a substantial understanding of their function3. By contrast, there are no structures of class D GPCRs, which are found exclusively in fungi where they regulate survival and reproduction. Here we determine the structure of a class D GPCR, the Saccharomyces cerevisiae pheromone receptor Ste2, in an active state coupled to the heterotrimeric G protein Gpa1–Ste4–Ste18. Ste2 was purified as a homodimer coupled to two G proteins. The dimer interface of Ste2 is formed by the N terminus, the transmembrane helices H1, H2 and H7, and the first extracellular loop ECL1. We establish a class D1 generic residue numbering system (CD1) to enable comparisons with orthologues and with other GPCR classes. The structure of Ste2 bears similarities in overall topology to class A GPCRs, but the transmembrane helix H4 is shifted by more than 20 Å and the G-protein-binding site is a shallow groove rather than a cleft. The structure provides a template for the design of novel drugs to target fungal GPCRs, which could be used to treat numerous intractable fungal diseases4.

Suggested Citation

  • Vaithish Velazhahan & Ning Ma & Gáspár Pándy-Szekeres & Albert J. Kooistra & Yang Lee & David E. Gloriam & Nagarajan Vaidehi & Christopher G. Tate, 2021. "Structure of the class D GPCR Ste2 dimer coupled to two G proteins," Nature, Nature, vol. 589(7840), pages 148-153, January.
    • Handle: RePEc:nat:nature:v:589:y:2021:i:7840:d:10.1038_s41586-020-2994-1
    DOI: 10.1038/s41586-020-2994-1
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    Cited by:

    1. Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021. "Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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