title: Structural basis for selectivity and diversity in angiotensin II receptors.
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 new selective ligands.
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.|Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.affiliation: Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, California 94025, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Batyuk
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Andrii
authors.initials: A
authors.lastname: Ishchenko
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.|Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: White
authors.affiliation: Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Nilkanth
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Anastasiia
authors.initials: A
authors.lastname: Sadybekov
authors.affiliation: MRL, Merck &Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
authors.forename: Beata
authors.initials: B
authors.lastname: Zamlynny
authors.affiliation: MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.affiliation: MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Hollenstein
authors.affiliation: Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany.|Department of Physics, University of Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tolstikova
authors.affiliation: Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, California 94025, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hunter
authors.affiliation: Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Weierstall
authors.affiliation: School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.affiliation: MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Moore
authors.affiliation: MRL, Merck &Co., Inc., 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Katz
authors.affiliation: MRL, Merck &Co., Inc., 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Shipman
authors.affiliation: MRL, Merck &Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Garcia-Calvo
authors.affiliation: MRL, Merck &Co., Inc., 503 Louise Lane, North Wales, Pennsylvania 19454, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.affiliation: MRL, Merck &Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Sheth
authors.affiliation: MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.|Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.|Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D015195:Drug Design; D020962:Heterotrimeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000235:genetics; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000071557:beta-Arrestins; D020962:Heterotrimeric GTP-Binding Proteins