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- PDB-9zxd: Structure of AT118-R nanobody in complex with the angiotensin II ... -

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Basic information

Entry
Database: PDB / ID: 9zxd
TitleStructure of AT118-R nanobody in complex with the angiotensin II type I receptor bound to L-162,313
Components
  • AT118-R nanobody,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion
  • BAG2 Anti-BRIL Fab Heavy Chain
  • BAG2 Anti-BRIL Fab Light Chain
KeywordsMEMBRANE PROTEIN / GPCR / nanobody
Function / homology
Function and homology information


angiotensin type I receptor activity / angiotensin type II receptor activity / regulation of renal sodium excretion / maintenance of blood vessel diameter homeostasis by renin-angiotensin / renin-angiotensin regulation of aldosterone production / phospholipase C-activating angiotensin-activated signaling pathway / bradykinin receptor binding / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / positive regulation of cholesterol metabolic process / low-density lipoprotein particle remodeling ...angiotensin type I receptor activity / angiotensin type II receptor activity / regulation of renal sodium excretion / maintenance of blood vessel diameter homeostasis by renin-angiotensin / renin-angiotensin regulation of aldosterone production / phospholipase C-activating angiotensin-activated signaling pathway / bradykinin receptor binding / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / positive regulation of cholesterol metabolic process / low-density lipoprotein particle remodeling / positive regulation of macrophage derived foam cell differentiation / regulation of systemic arterial blood pressure by renin-angiotensin / Rho protein signal transduction / regulation of vasoconstriction / kidney development / blood vessel diameter maintenance / angiotensin-activated signaling pathway / Peptide ligand-binding receptors / calcium-mediated signaling / cell chemotaxis / regulation of cell growth / electron transport chain / regulation of blood pressure / positive regulation of reactive oxygen species metabolic process / positive regulation of inflammatory response / phospholipase C-activating G protein-coupled receptor signaling pathway / regulation of cell population proliferation / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / regulation of inflammatory response / positive regulation of cytosolic calcium ion concentration / G alpha (q) signalling events / electron transfer activity / periplasmic space / inflammatory response / iron ion binding / G protein-coupled receptor signaling pathway / protein heterodimerization activity / heme binding / symbiont entry into host cell / membrane / plasma membrane
Similarity search - Function
Angiotensin II receptor type 1 / Angiotensin II receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like ...Angiotensin II receptor type 1 / Angiotensin II receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
: / CHOLESTEROL HEMISUCCINATE / Soluble cytochrome b562 / Type-1 angiotensin II receptor
Similarity search - Component
Biological speciessynthetic construct (others)
Homo sapiens (human)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSkiba, M.A. / Kruse, A.C.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)K99HD110612 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA260415 United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)R21HD101596 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL176532 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Activation of the angiotensin II type I receptor by a nonpeptide agonist.
Authors: Meredith A Skiba / Jinghan Liu / Pengxiang Shen / Jihee Kim / Elizabeth Wren / Morgan S A Gilman / Dean Staus / Conor McMahon / Jeffrey S Smith / Robert J Lefkowitz / Daniel Kahne / Laura M ...Authors: Meredith A Skiba / Jinghan Liu / Pengxiang Shen / Jihee Kim / Elizabeth Wren / Morgan S A Gilman / Dean Staus / Conor McMahon / Jeffrey S Smith / Robert J Lefkowitz / Daniel Kahne / Laura M Wingler / Andrew C Kruse /
Abstract: The angiotensin II type I receptor (AT1R) is a G protein-coupled receptor that regulates the cardiovascular system and as a result is one of the most successful pharmacological targets for the ...The angiotensin II type I receptor (AT1R) is a G protein-coupled receptor that regulates the cardiovascular system and as a result is one of the most successful pharmacological targets for the treatment of hypertension. Within the angiotensin receptor pharmacological landscape, agonists are peptide ligands, whereas potent antagonists are predominantly small molecules. Three decades ago, a small number of nonpeptide AT1R agonists were identified. These molecules largely share a chemical scaffold with AT1R antagonists, but appeared to interact with the receptor in a manner that diverges from both antagonists and peptide agonists. Here, we revisit L-162,313, the prototype nonpeptide AT1R agonist and determine how the antagonist-like chemical scaffold acts as an agonist. L-162,313 binds similarly to AT1R antagonists, but unlike antagonists, it engages the same activation switches as peptide agonists. We map the spatial relationship required for activation of AT1R by nonpeptide agonists and used this information to design a small library of L-162,313 derivatives. These rationally designed derivatives had the expected reduced or enhanced potency based on the structural basis for activation. Our data resolve a long-standing pharmacological mystery and provide a foundation for generating more efficacious small molecule AT1R agonists.
History
DepositionJan 3, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
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Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.1Aug 12, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: AT118-R nanobody,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion
C: BAG2 Anti-BRIL Fab Heavy Chain
D: BAG2 Anti-BRIL Fab Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,5405
Polymers113,4703
Non-polymers1,0702
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein AT118-R nanobody,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion


Mass: 65389.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others), (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: AGTR1, AGTR1A, AGTR1B, AT2R1, AT2R1B, cybC / Production host: Homo sapiens (human) / References: UniProt: P30556, UniProt: P0ABE7
#2: Antibody BAG2 Anti-BRIL Fab Heavy Chain


Mass: 24539.314 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)
#3: Antibody BAG2 Anti-BRIL Fab Light Chain


Mass: 23541.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#5: Chemical ChemComp-A1C42 / butyl [3-{4-[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl]phenyl}-5-(2-methylpropyl)thiophene-2-sulfonyl]carbamate / L-162,313


Mass: 582.777 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H38N4O4S2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Structure of AT118-R Nanobody in Complex with the Angiotensin II Type I Receptor bound to L-162,313COMPLEX#1-#30MULTIPLE SOURCES
2AT118-R nanobody fused to Type-1 angiotensin II receptor with Soluble cytochrome b562 insertionCOMPLEX#11RECOMBINANT
3BAG2 Anti-BRIL FabCOMPLEX#2-#31RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
32Escherichia coli (E. coli)562
42synthetic construct (others)32630
53synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
22Homo sapiens (human)9606Expi293
33Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 63.88 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 6182
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategoryImage processing-ID
1cryoSPARC3particle selection1
2PHENIX1.21.1_5286model refinement
3SerialEM4.0.5image acquisition1
5cryoSPARC3CTF correction1
10cryoSPARC3initial Euler assignment1
11cryoSPARC3final Euler assignment1
13cryoSPARC33D reconstruction1
14cryoSPARC3particle selection2
15cryoSPARC3CTF correction2
16cryoSPARC3initial Euler assignment2
17cryoSPARC3final Euler assignment2
19cryoSPARC33D reconstruction2
Image processing
IDImage recording-ID
11
21
CTF correction
IDEM image processing-IDType
11PHASE FLIPPING AND AMPLITUDE CORRECTION
22PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selection
IDImage processing-IDNum. of particles selected
113596857
221830526
3D reconstruction
IDResolution (Å)Resolution methodNum. of particlesImage processing-IDEntry-IDSymmetry type
13.2FSC 0.143 CUT-OFF46427519ZXDPOINT
23.2FSC 0.143 CUT-OFF46427519ZXDPOINT
33.2FSC 0.143 CUT-OFF46427529ZXDPOINT
43.2FSC 0.143 CUT-OFF46427529ZXDPOINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045883
ELECTRON MICROSCOPYf_angle_d0.5648000
ELECTRON MICROSCOPYf_dihedral_angle_d7.676889
ELECTRON MICROSCOPYf_chiral_restr0.04897
ELECTRON MICROSCOPYf_plane_restr0.004985

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