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-Calvo; Sujata Sharma; Payal Sheth; Stephen M. Soisson; Raymond C. Stevens; Vsevolod Katritch; Vadim Cherezov

doi:10.1038/nature22035

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

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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 language	English (US)
Pages (from-to)	327-332
Number of pages	6
Journal	Nature
Volume	544
Issue number	7650
DOIs	https://doi.org/10.1038/nature22035
State	Published - Apr 20 2017

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Zhang, H., Han, G. W., Batyuk, A., Ishchenko, A., White, K. L., Patel, N., Sadybekov, A., Zamlynny, B., Rudd, M. T., Hollenstein, K., Tolstikova, A., White, T. A., Hunter, M. S., Weierstall, U., Liu, W., Babaoglu, K., Moore, E. L., Katz, R. D., Shipman, J. M., ... Cherezov, V. (2017). Structural basis for selectivity and diversity in angiotensin II receptors. Nature, 544(7650), 327-332. https://doi.org/10.1038/nature22035

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

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title = "Structural basis for selectivity and diversity in angiotensin II receptors",

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.",

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

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AU - Patel, Nilkanth

AU - Sadybekov, Anastasiia

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AU - Rudd, Michael T.

AU - Hollenstein, Kaspar

AU - Tolstikova, Alexandra

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AU - Weierstall, Uwe

AU - Liu, Wei

AU - Babaoglu, Kerim

AU - Moore, Eric L.

AU - Katz, Ryan D.

AU - Shipman, Jennifer M.

AU - Garcia-Calvo, Margarita

AU - Sharma, Sujata

AU - Sheth, Payal

AU - Soisson, Stephen M.

AU - Stevens, Raymond C.

AU - Katritch, Vsevolod

AU - Cherezov, Vadim

PY - 2017/4/20

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N2 - 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.

AB - 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.

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Structural basis for selectivity and diversity in angiotensin II receptors

Abstract

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XFEL structure of human angiotensin II type 2 receptor (Orthorhombic form) in complex with compound 1 (N-benzyl-N-(2-ethyl-4-oxo-3-{[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl}-3,4-dihydroquinazolin-6-yl)thiophene-2-carboxamide)

XFEL structure of human angiotensin II type 2 receptor (Monoclinic form) in complex with compound 1 (N-benzyl-N-(2-ethyl-4-oxo-3-{[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl])

Synchrotron structure of human angiotensin II type 2 receptor in complex with compound 2 (N-[(furan-2-yl)methyl]-N-(4-oxo-2-propyl-3-{[2'-(2H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl}-3,4-dihydroquinazolin-6-yl)benzamide)

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Structural basis for selectivity and diversity in angiotensin II receptors

Abstract

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XFEL structure of human angiotensin II type 2 receptor (Orthorhombic form) in complex with compound 1 (N-benzyl-N-(2-ethyl-4-oxo-3-{[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl}-3,4-dihydroquinazolin-6-yl)thiophene-2-carboxamide)

XFEL structure of human angiotensin II type 2 receptor (Monoclinic form) in complex with compound 1 (N-benzyl-N-(2-ethyl-4-oxo-3-{[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl])

Synchrotron structure of human angiotensin II type 2 receptor in complex with compound 2 (N-[(furan-2-yl)methyl]-N-(4-oxo-2-propyl-3-{[2'-(2H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl}-3,4-dihydroquinazolin-6-yl)benzamide)

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