Structural basis for selectivity and diversity in angiotensin II receptors

Haitao Zhang, Gye Won Han, Alexander Batyuk, Andrii Ishchenko, Kate L. White, Nilkanth Patel, Anastasiia Sadybekov, Beata Zamlynny, Michael T. Rudd, Kaspar Hollenstein, Alexandra Tolstikova, Thomas A. White, Mark S. Hunter, Uwe Weierstall, Wei Liu, Kerim Babaoglu, Eric L. Moore, Ryan D. Katz, Jennifer M. Shipman, Margarita Garcia-CalvoSujata Sharma, Payal Sheth, Stephen M. Soisson, Raymond C. Stevens, Vsevolod Katritch, Vadim Cherezov

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

The angiotensin II receptors AT1 R and AT2 R serve as key components of the renin-angiotensin-aldosterone system. AT1 R has a central role in the regulation of blood pressure, but the function of AT2 R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT2 R bound to an AT2 R-selective ligand and to an AT 1 R/AT2 R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.

Original languageEnglish (US)
Pages (from-to)327-332
Number of pages6
JournalNature
Volume544
Issue number7650
DOIs
StatePublished - Apr 20 2017

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Angiotensin Receptors
Ligands
Arrestins
Structure-Activity Relationship
Renin-Angiotensin System
GTP-Binding Proteins
Mutagenesis
Blood Pressure

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Zhang, H., Han, G. W., Batyuk, A., Ishchenko, A., White, K. L., Patel, N., ... Cherezov, V. (2017). Structural basis for selectivity and diversity in angiotensin II receptors. Nature, 544(7650), 327-332. https://doi.org/10.1038/nature22035

Structural basis for selectivity and diversity in angiotensin II receptors. / Zhang, Haitao; Han, Gye Won; Batyuk, Alexander; Ishchenko, Andrii; White, Kate L.; Patel, Nilkanth; Sadybekov, Anastasiia; Zamlynny, Beata; Rudd, Michael T.; Hollenstein, Kaspar; Tolstikova, Alexandra; White, Thomas A.; Hunter, Mark S.; Weierstall, Uwe; Liu, Wei; Babaoglu, Kerim; Moore, Eric L.; Katz, Ryan D.; Shipman, Jennifer M.; Garcia-Calvo, Margarita; Sharma, Sujata; Sheth, Payal; Soisson, Stephen M.; Stevens, Raymond C.; Katritch, Vsevolod; Cherezov, Vadim.

In: Nature, Vol. 544, No. 7650, 20.04.2017, p. 327-332.

Research output: Contribution to journalArticle

Zhang, H, Han, GW, Batyuk, A, Ishchenko, A, White, KL, Patel, N, Sadybekov, A, Zamlynny, B, Rudd, MT, Hollenstein, K, Tolstikova, A, White, TA, Hunter, MS, Weierstall, U, Liu, W, Babaoglu, K, Moore, EL, Katz, RD, Shipman, JM, Garcia-Calvo, M, Sharma, S, Sheth, P, Soisson, SM, Stevens, RC, Katritch, V & Cherezov, V 2017, 'Structural basis for selectivity and diversity in angiotensin II receptors', Nature, vol. 544, no. 7650, pp. 327-332. https://doi.org/10.1038/nature22035
Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N et al. Structural basis for selectivity and diversity in angiotensin II receptors. Nature. 2017 Apr 20;544(7650):327-332. https://doi.org/10.1038/nature22035
Zhang, Haitao ; Han, Gye Won ; Batyuk, Alexander ; Ishchenko, Andrii ; White, Kate L. ; Patel, Nilkanth ; Sadybekov, Anastasiia ; Zamlynny, Beata ; Rudd, Michael T. ; Hollenstein, Kaspar ; Tolstikova, Alexandra ; White, Thomas A. ; Hunter, Mark S. ; Weierstall, Uwe ; Liu, Wei ; Babaoglu, Kerim ; Moore, Eric L. ; Katz, Ryan D. ; Shipman, Jennifer M. ; Garcia-Calvo, Margarita ; Sharma, Sujata ; Sheth, Payal ; Soisson, Stephen M. ; Stevens, Raymond C. ; Katritch, Vsevolod ; Cherezov, Vadim. / Structural basis for selectivity and diversity in angiotensin II receptors. In: Nature. 2017 ; Vol. 544, No. 7650. pp. 327-332.
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