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Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics

Author

Listed:
  • Xinyu Xu

    (Tsinghua University
    Tsinghua University)

  • Jeremy Shonberg

    (Friedrich-Alexander University Erlangen-Nurnberg)

  • Jonas Kaindl

    (Friedrich-Alexander University Erlangen-Nurnberg)

  • Mary J. Clark

    (University of California San Diego School of Medicine)

  • Anne Stößel

    (Friedrich-Alexander University Erlangen-Nurnberg)

  • Luis Maul

    (Friedrich-Alexander University Erlangen-Nurnberg)

  • Daniel Mayer

    (University of California San Diego School of Medicine)

  • Harald Hübner

    (Friedrich-Alexander University Erlangen-Nurnberg)

  • Kunio Hirata

    (RIKEN/SPring-8 Center
    Japan Science and Technology Agency)

  • A. J. Venkatakrishnan

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Ron O. Dror

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Brian K. Kobilka

    (Stanford University School of Medicine)

  • Roger K. Sunahara

    (University of California San Diego School of Medicine)

  • Xiangyu Liu

    (Tsinghua University
    Tsinghua University
    Peking University)

  • Peter Gmeiner

    (Friedrich-Alexander University Erlangen-Nurnberg)

Abstract

G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form the orthosteric binding pocket for epinephrine and norepinephrine in the β1 and β2 adrenergic receptors (β1AR and β2AR) are identical. Here, to examine the effect of conformational restriction on ligand binding kinetics, we synthesized a constrained form of epinephrine. Surprisingly, the constrained epinephrine exhibits over 100-fold selectivity for the β2AR over the β1AR. We provide evidence that the selectivity may be due to reduced ligand flexibility that enhances the association rate for the β2AR, as well as a less stable binding pocket for constrained epinephrine in the β1AR. The differences in the amino acid sequence of the extracellular vestibule of the β1AR allosterically alter the shape and stability of the binding pocket, resulting in a marked difference in affinity compared to the β2AR. These studies suggest that for receptors containing identical binding pocket residues, the binding selectivity may be influenced in an allosteric manner by surrounding residues, like those of the extracellular loops (ECLs) that form the vestibule. Exploiting these allosteric influences may facilitate the development of more subtype-selective ligands for GPCRs.

Suggested Citation

  • Xinyu Xu & Jeremy Shonberg & Jonas Kaindl & Mary J. Clark & Anne Stößel & Luis Maul & Daniel Mayer & Harald Hübner & Kunio Hirata & A. J. Venkatakrishnan & Ron O. Dror & Brian K. Kobilka & Roger K. Su, 2023. "Constrained catecholamines gain β2AR selectivity through allosteric effects on pocket dynamics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37808-y
    DOI: 10.1038/s41467-023-37808-y
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    References listed on IDEAS

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    1. Brian T. DeVree & Jacob P. Mahoney & Gisselle A. Vélez-Ruiz & Soren G. F. Rasmussen & Adam J. Kuszak & Elin Edwald & Juan-Jose Fung & Aashish Manglik & Matthieu Masureel & Yang Du & Rachel A. Matt & E, 2016. "Allosteric coupling from G protein to the agonist-binding pocket in GPCRs," Nature, Nature, vol. 535(7610), pages 182-186, July.
    2. Daniel M. Rosenbaum & Cheng Zhang & Joseph A. Lyons & Ralph Holl & David Aragao & Daniel H. Arlow & Søren G. F. Rasmussen & Hee-Jung Choi & Brian T. DeVree & Roger K. Sunahara & Pil Seok Chae & Samuel, 2011. "Structure and function of an irreversible agonist-β2 adrenoceptor complex," Nature, Nature, vol. 469(7329), pages 236-240, January.
    3. Aaron M. Ring & Aashish Manglik & Andrew C. Kruse & Michael D. Enos & William I. Weis & K. Christopher Garcia & Brian K. Kobilka, 2013. "Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody," Nature, Nature, vol. 502(7472), pages 575-579, October.
    4. Harald Hübner & Tamara Schellhorn & Marie Gienger & Carolin Schaab & Jonas Kaindl & Laurin Leeb & Timothy Clark & Dorothee Möller & Peter Gmeiner, 2016. "Structure-guided development of heterodimer-selective GPCR ligands," Nature Communications, Nature, vol. 7(1), pages 1-12, November.
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    Cited by:

    1. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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