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- EMDB-74919: Structure of AT118-R nanobody in complex with the angiotensin II ... -

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Basic information

Entry
Database: EMDB / ID: EMD-74919
TitleStructure of AT118-R nanobody in complex with the angiotensin II type I receptor bound to losartan
Map datalocal map
Sample
  • Complex: Structure of AT118-R Nanobody in Complex with the Angiotensin II Type I Receptor and Losartan
    • Complex: Nanobody AT118-R fused to Type-1 angiotensin II receptor with inserted Soluble cytochrome b562
      • Protein or peptide: Nanobody AT118-R,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion
    • Complex: BAG2 Anti-BRIL Fab
      • Protein or peptide: BAG2 Anti-BRIL Fab Heavy Chain
      • Protein or peptide: BAG2 Anti-BRIL Fab Light Chain
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
KeywordsGPCR / nanobody / MEMBRANE PROTEIN
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
Soluble cytochrome b562 / Type-1 angiotensin II receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsSkiba MA / Gilman MSA / Kruse AC
Funding support United States, 4 items
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, 2026-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateAug 12, 2026-
Current statusAug 12, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74919.png

Downloads & links

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Map

FileDownload / File: emd_74919.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationlocal map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 352 pix.
= 290.4 Å		0.83 Å/pix.
x 352 pix.
= 290.4 Å		0.83 Å/pix.
x 352 pix.
= 290.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.26
Minimum - Maximum-1.3967481 - 1.9230179
Average (Standard dev.)0.0001744011 (±0.023587655)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 290.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: global map

Fileemd_74919_additional_1.map
Annotationglobal map
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Additional map: global half map

Fileemd_74919_additional_2.map
Annotationglobal half map
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Additional map: global half map

Fileemd_74919_additional_3.map
Annotationglobal half map
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Half map: local half map

Fileemd_74919_half_map_1.map
Annotationlocal half map
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Histogram

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Half map: local half map

Fileemd_74919_half_map_2.map
Annotationlocal half map
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Sample components

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Entire : Structure of AT118-R Nanobody in Complex with the Angiotensin II ...

EntireName: Structure of AT118-R Nanobody in Complex with the Angiotensin II Type I Receptor and Losartan
Components
  • Complex: Structure of AT118-R Nanobody in Complex with the Angiotensin II Type I Receptor and Losartan
    • Complex: Nanobody AT118-R fused to Type-1 angiotensin II receptor with inserted Soluble cytochrome b562
      • Protein or peptide: Nanobody AT118-R,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion
    • Complex: BAG2 Anti-BRIL Fab
      • Protein or peptide: BAG2 Anti-BRIL Fab Heavy Chain
      • Protein or peptide: BAG2 Anti-BRIL Fab Light Chain
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol

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Supramolecule #1: Structure of AT118-R Nanobody in Complex with the Angiotensin II ...

SupramoleculeName: Structure of AT118-R Nanobody in Complex with the Angiotensin II Type I Receptor and Losartan
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Nanobody AT118-R fused to Type-1 angiotensin II receptor with ins...

SupramoleculeName: Nanobody AT118-R fused to Type-1 angiotensin II receptor with inserted Soluble cytochrome b562
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: BAG2 Anti-BRIL Fab

SupramoleculeName: BAG2 Anti-BRIL Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: Nanobody AT118-R,Type-1 angiotensin II receptor with Soluble cyto...

MacromoleculeName: Nanobody AT118-R,Type-1 angiotensin II receptor with Soluble cytochrome b562 insertion
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.389816 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLQESGGG LVQAGGSLRL SCAASGYIYR KYRMGWYRQA PGKEREFVAG INGGSSTNYA DSVKGRFTIS RDNAKNTVYL QMNSLKPED TAVYYCAAYR IVRGLLVYWG QGTQVTVSSL EGGSGEDQVD PRLIDGKILN SSTEDGIKRI QDDCPKAGRH N YIFVMIPT ...String:
QVQLQESGGG LVQAGGSLRL SCAASGYIYR KYRMGWYRQA PGKEREFVAG INGGSSTNYA DSVKGRFTIS RDNAKNTVYL QMNSLKPED TAVYYCAAYR IVRGLLVYWG QGTQVTVSSL EGGSGEDQVD PRLIDGKILN SSTEDGIKRI QDDCPKAGRH N YIFVMIPT LYSIIFVVGI FGNSLVVIVI YFYMKLKTVA SVFLLNLALA DLCFLLTLPL WAVYTAMEYR WPFGNYLCKI AS ASVSFNL YASVFLLTCL SIDRYLAIVH PMKSRLRRTM LVAKVTCIII WLLAGLASLP AIIHRNVFFI ENTNITVCAF HYE SQNSTL PIGLGLTKNI LGFLFPFLII LTSYTLIWKA LKKAYDLEDN WETLNDNLKV IEKADNAAQV KDALTKMRAA ALDA QKATP PKLEDKSPDS PEMKDFRHGF DILVGQIDDA LKLANEGKVK EAQAAAEQLK TTRNAYIQKY LERARSTLDK LNDDI FKII MAIVLFFFFS WIPHQIFTFL DVLIQLGIIR DCRIADIVDT AMPITICIAY FNNCLNPLFY GFLGKKFKRY FLQLLK YGG SSLEVLFQGP TETSQVAPA

UniProtKB: Type-1 angiotensin II receptor, Soluble cytochrome b562, Type-1 angiotensin II receptor

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Macromolecule #2: BAG2 Anti-BRIL Fab Heavy Chain

MacromoleculeName: BAG2 Anti-BRIL Fab Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 24.539314 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVVDFSLHWV RQAPGKGLEW VAYISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARWGYWPGEP WWKAFDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCD

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Macromolecule #3: BAG2 Anti-BRIL Fab Light Chain

MacromoleculeName: BAG2 Anti-BRIL Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 23.541164 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]ph...

MacromoleculeName: [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
type: ligand / ID: 5 / Number of copies: 1 / Formula: LSN
Molecular weightTheoretical: 422.911 Da
Chemical component information

ChemComp-LSN:
[2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol / medication*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Slit width: 20 eV
SoftwareName: SerialEM (ver. 4.0.5)
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 5150 / Average electron dose: 62.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.9 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1830526
CTF correctionSoftware - Name: cryoSPARC (ver. 3) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Ab Initio Model
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 598896
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: cryoSPARC (ver. 3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3)

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