Journal Article

PUBDB-2017-11813

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural basis for selectivity and diversity in angiotensin II receptors

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.CFEL* ; White, T. A.CFEL*DESY* ; Hunter, M. S. ; Weierstall, U.Extern* ; Liu, W. ; Babaoglu, K. ; Moore, E. L. ; Katz, R. D. ; Shipman, J. M. ; Garcia-Calvo, M. ; Sharma, S. ; Sheth, P. ; Soisson, S. M. ; Stevens, R. C. ; Katritch, V. ; Cherezov, V. (Corresponding author)

2017
Nature Publ. Group London [u.a.]

This record in other databases:        

Please use a persistent id in citations: doi:10.1038/nature22035

Abstract: The angiotensin II receptors AT1R and AT2R serve as key components of the renin–angiotensin–aldosterone system. AT1R has a central role in the regulation of blood pressure, but the function of AT2R 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 AT2R bound to an AT2R-selective ligand and to an AT1R/AT2R 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 newselective ligands.

Note: © Macmillan Publishers Limited, part of Springer Nature ; Post referee fulltext in progress; Embargo 6 months from publication

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Contributing Institute(s):

1. FS-CFEL-1 (Group Leader: Henry Chapman) (CFEL-I)
2. CFEL-Coherent X-Ray Imaging (FS-CFEL-1)

Research Program(s):

1. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)
2. X-probe - Advanced XFEL and Synchrotron based Probes of Protein Structure and Dynamics (637295) (637295)

Experiment(s):

1. Measurement at external facility

Appears in the scientific report 2017

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Database coverage:
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