Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist

Matthieu Masureel, Yaozhong Zou, Louis Philippe Picard, Emma van der Westhuizen, Jacob P. Mahoney, João P.G.L.M. Rodrigues, Thomas J. Mildorf, Ron O. Dror, David E. Shaw, Michel Bouvier, Els Pardon, Jan Steyaert, Roger K. Sunahara, William I. Weis, Cheng Zhang, Brian K. Kobilka

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol’s safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204 5.43 and Asn293 6.55 . Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.

Original languageEnglish
Pages (from-to)1059-1066
Number of pages8
JournalNature Chemical Biology
Volume14
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Cite this

Masureel, M., Zou, Y., Picard, L. P., van der Westhuizen, E., Mahoney, J. P., Rodrigues, J. P. G. L. M., ... Kobilka, B. K. (2018). Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist. Nature Chemical Biology, 14(11), 1059-1066. https://doi.org/10.1038/s41589-018-0145-x
Masureel, Matthieu ; Zou, Yaozhong ; Picard, Louis Philippe ; van der Westhuizen, Emma ; Mahoney, Jacob P. ; Rodrigues, João P.G.L.M. ; Mildorf, Thomas J. ; Dror, Ron O. ; Shaw, David E. ; Bouvier, Michel ; Pardon, Els ; Steyaert, Jan ; Sunahara, Roger K. ; Weis, William I. ; Zhang, Cheng ; Kobilka, Brian K. / Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist. In: Nature Chemical Biology. 2018 ; Vol. 14, No. 11. pp. 1059-1066.
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abstract = "Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol’s safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204 5.43 and Asn293 6.55 . Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.",
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Masureel, M, Zou, Y, Picard, LP, van der Westhuizen, E, Mahoney, JP, Rodrigues, JPGLM, Mildorf, TJ, Dror, RO, Shaw, DE, Bouvier, M, Pardon, E, Steyaert, J, Sunahara, RK, Weis, WI, Zhang, C & Kobilka, BK 2018, 'Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist' Nature Chemical Biology, vol. 14, no. 11, pp. 1059-1066. https://doi.org/10.1038/s41589-018-0145-x

Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist. / Masureel, Matthieu; Zou, Yaozhong; Picard, Louis Philippe; van der Westhuizen, Emma; Mahoney, Jacob P.; Rodrigues, João P.G.L.M.; Mildorf, Thomas J.; Dror, Ron O.; Shaw, David E.; Bouvier, Michel; Pardon, Els; Steyaert, Jan; Sunahara, Roger K.; Weis, William I.; Zhang, Cheng; Kobilka, Brian K.

In: Nature Chemical Biology, Vol. 14, No. 11, 01.11.2018, p. 1059-1066.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Masureel, Matthieu

AU - Zou, Yaozhong

AU - Picard, Louis Philippe

AU - van der Westhuizen, Emma

AU - Mahoney, Jacob P.

AU - Rodrigues, João P.G.L.M.

AU - Mildorf, Thomas J.

AU - Dror, Ron O.

AU - Shaw, David E.

AU - Bouvier, Michel

AU - Pardon, Els

AU - Steyaert, Jan

AU - Sunahara, Roger K.

AU - Weis, William I.

AU - Zhang, Cheng

AU - Kobilka, Brian K.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol’s safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204 5.43 and Asn293 6.55 . Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.

AB - Salmeterol is a partial agonist for the β 2 adrenergic receptor (β 2 AR) and the first long-acting β 2 AR agonist to be widely used clinically for the treatment of asthma and chronic obstructive pulmonary disease. Salmeterol’s safety and mechanism of action have both been controversial. To understand its unusual pharmacological action and partial agonism, we obtained the crystal structure of salmeterol-bound β 2 AR in complex with an active-state-stabilizing nanobody. The structure reveals the location of the salmeterol exosite, where sequence differences between β 1 AR and β 2 AR explain the high receptor-subtype selectivity. A structural comparison with the β 2 AR bound to the full agonist epinephrine reveals differences in the hydrogen-bond network involving residues Ser204 5.43 and Asn293 6.55 . Mutagenesis and biophysical studies suggested that these interactions lead to a distinct active-state conformation that is responsible for the partial efficacy of G-protein activation and the limited β-arrestin recruitment for salmeterol.

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JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

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