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Structure and dynamics of the active Gs-coupled human secretin receptor

Author

Listed:
  • Maoqing Dong

    (Mayo Clinic)

  • Giuseppe Deganutti

    (University of Essex
    Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Alison Gingell Building, Coventry University)

  • Sarah J. Piper

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Yi-Lynn Liang

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Maryam Khoshouei

    (Max Planck Institute of Biochemistry
    Novartis Institutes for Biomedical Research, Novartis Pharma AG)

  • Matthew J. Belousoff

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Kaleeckal G. Harikumar

    (Mayo Clinic)

  • Christopher A. Reynolds

    (University of Essex)

  • Alisa Glukhova

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Sebastian G. B. Furness

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Arthur Christopoulos

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Radostin Danev

    (University of Tokyo)

  • Denise Wootten

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Patrick M. Sexton

    (Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Laurence J. Miller

    (Mayo Clinic)

Abstract

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17791-4
    DOI: 10.1038/s41467-020-17791-4
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    Cited by:

    1. Kaleeckal G. Harikumar & Sarah J. Piper & Arthur Christopoulos & Denise Wootten & Patrick M. Sexton & Laurence J. Miller, 2024. "Impact of secretin receptor homo-dimerization on natural ligand binding," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. 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.
    5. Chaehee Park & Jinuk Kim & Seung-Bum Ko & Yeol Kyo Choi & Hyeongseop Jeong & Hyeonuk Woo & Hyunook Kang & Injin Bang & Sang Ah Kim & Tae-Young Yoon & Chaok Seok & Wonpil Im & Hee-Jung Choi, 2022. "Structural basis of neuropeptide Y signaling through Y1 receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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