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Understanding VPAC receptor family peptide binding and selectivity

Author

Listed:
  • Sarah J. Piper

    (Monash University
    Monash University)

  • Giuseppe Deganutti

    (Coventry University)

  • Jessica Lu

    (Monash University
    Monash University)

  • Peishen Zhao

    (Monash University
    Monash University)

  • Yi-Lynn Liang

    (Monash University
    Confo TherapeuticsTechnologiepark 94)

  • Yao Lu

    (Monash University
    Monash University)

  • Madeleine M. Fletcher

    (Monash University
    GlaxoSmithKline)

  • Mohammed Akhter Hossain

    (The University of Melbourne)

  • Arthur Christopoulos

    (Monash University
    Monash University)

  • Christopher A. Reynolds

    (Coventry University
    University of Essex)

  • Radostin Danev

    (University of Tokyo)

  • Patrick M. Sexton

    (Monash University
    Monash University)

  • Denise Wootten

    (Monash University
    Monash University)

Abstract

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.

Suggested Citation

  • Sarah J. Piper & Giuseppe Deganutti & Jessica Lu & Peishen Zhao & Yi-Lynn Liang & Yao Lu & Madeleine M. Fletcher & Mohammed Akhter Hossain & Arthur Christopoulos & Christopher A. Reynolds & Radostin D, 2022. "Understanding VPAC receptor family peptide binding and selectivity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34629-3
    DOI: 10.1038/s41467-022-34629-3
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    References listed on IDEAS

    as
    1. Jia Duan & Dan-dan Shen & X. Edward Zhou & Peng Bi & Qiu-feng Liu & Yang-xia Tan & You-wen Zhuang & Hui-bing Zhang & Pei-yu Xu & Si-Jie Huang & Shan-shan Ma & Xin-heng He & Karsten Melcher & Yan Zhang, 2020. "Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Maoqing Dong & Giuseppe Deganutti & Sarah J. Piper & Yi-Lynn Liang & Maryam Khoshouei & Matthew J. Belousoff & Kaleeckal G. Harikumar & Christopher A. Reynolds & Alisa Glukhova & Sebastian G. B. Furne, 2020. "Structure and dynamics of the active Gs-coupled human secretin receptor," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. Yi-Lynn Liang & Maryam Khoshouei & Alisa Glukhova & Sebastian G. B. Furness & Peishen Zhao & Lachlan Clydesdale & Cassandra Koole & Tin T. Truong & David M. Thal & Saifei Lei & Mazdak Radjainia & Rado, 2018. "Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex," Nature, Nature, vol. 555(7694), pages 121-125, March.
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