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- EMDB-63629: CryoEM structure of the alpha1AAR complex with silodosin -

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Basic information

Entry
Database: EMDB / ID: EMD-63629
TitleCryoEM structure of the alpha1AAR complex with silodosin
Map data
Sample
  • Complex: CryoEM structure of the the alpha1AAR complex with silodosin
    • Protein or peptide: Alpha-1A adrenergic receptor
  • Ligand: Silodosin
KeywordsGPCR / Alpha1AAR / Silodosin / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / pilomotor reflex / phospholipase C-activating adrenergic receptor signaling pathway / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of action potential ...negative regulation of heart rate involved in baroreceptor response to increased systemic arterial blood pressure / alpha1-adrenergic receptor activity / norepinephrine-epinephrine vasoconstriction involved in regulation of systemic arterial blood pressure / positive regulation of heart rate by epinephrine-norepinephrine / positive regulation of the force of heart contraction by epinephrine-norepinephrine / pilomotor reflex / phospholipase C-activating adrenergic receptor signaling pathway / neuron-glial cell signaling / cell growth involved in cardiac muscle cell development / positive regulation of action potential / positive regulation of smooth muscle contraction / adult heart development / Adrenoceptors / positive regulation of cardiac muscle hypertrophy / smooth muscle contraction / adenylate cyclase-activating adrenergic receptor signaling pathway / response to hormone / positive regulation of vasoconstriction / positive regulation of cardiac muscle contraction / negative regulation of autophagy / positive regulation of synaptic transmission, GABAergic / caveola / MAPK cascade / G alpha (12/13) signalling events / cell-cell signaling / positive regulation of cytosolic calcium ion concentration / phospholipase C-activating G protein-coupled receptor signaling pathway / nuclear membrane / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / intracellular signal transduction / G protein-coupled receptor signaling pathway / protein heterodimerization activity / response to xenobiotic stimulus / negative regulation of cell population proliferation / intracellular membrane-bounded organelle / apoptotic process / signal transduction / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Alpha 1A adrenoceptor / Adrenoceptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Alpha-1A adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsLiu SS / Guo Q / Tao YY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Biol Chem / Year: 2025
Title: Molecular mechanism of antagonists recognition and regulation of the α- adrenoceptor. (α-Adrenoceptor Antagonist Recognition).
Authors: Sisi Liu / Haizhan Jiao / Yuyong Tao / Dandan Wang / Qiong Guo /
Abstract: The α-adrenoceptor (αAR) is a critically important class of G protein-coupled receptors (GPCRs), comprising three subtypes: αAR, αAR, and αAR. Currently, drugs targeting αAR have been used in ...The α-adrenoceptor (αAR) is a critically important class of G protein-coupled receptors (GPCRs), comprising three subtypes: αAR, αAR, and αAR. Currently, drugs targeting αAR have been used in the treatment of various diseases. Notably, antagonists of αAR play a pivotal role in the management of benign prostatic hyperplasia (BPH). In recent years, researchers have developed selective antagonists for the αAR subtype that have a minimal impact on blood pressure for the treatment of BPH. However, these agents still exhibit certain side effects, necessitating the continuous development of new medications to mitigate adverse reactions while achieving more precise regulation. We report the cryo-EM structures of the αAR selective antagonist doxazosin and the αAR subtype selective antagonist silodosin in complex with αAR, demonstrating that M292 and V185 are key residues that confer subtype selectivity to silodosin. Additionally, modifications to αAR enhanced silodosin's inhibitory efficacy against αAR. These findings deepen our understanding of the recognition patterns of αAR antagonists, revealing the molecular principles underlying the selective binding of silodosin to αAR and promoting further research and development of subtype selective drugs targeting αAR.
History
DepositionMar 4, 2025-
Header (metadata) releaseJul 2, 2025-
Map releaseJul 2, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63629.png

Downloads & links

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Map

FileDownload / File: emd_63629.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 300 pix.
= 247.8 Å		0.83 Å/pix.
x 300 pix.
= 247.8 Å		0.83 Å/pix.
x 300 pix.
= 247.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0767
Minimum - Maximum-1.9582818 - 2.3273075
Average (Standard dev.)-0.00015397345 (±0.0386754)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 247.79999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_63629_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_63629_half_map_2.map
Projections & Slices
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Sample components

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Entire : CryoEM structure of the the alpha1AAR complex with silodosin

EntireName: CryoEM structure of the the alpha1AAR complex with silodosin
Components
  • Complex: CryoEM structure of the the alpha1AAR complex with silodosin
    • Protein or peptide: Alpha-1A adrenergic receptor
  • Ligand: Silodosin

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Supramolecule #1: CryoEM structure of the the alpha1AAR complex with silodosin

SupramoleculeName: CryoEM structure of the the alpha1AAR complex with silodosin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Alpha-1A adrenergic receptor

MacromoleculeName: Alpha-1A adrenergic receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.7925 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: APVNISKAIL LGVILGGLIL FGVLGNILVI LSVACHRHLH SVTHYYIVNL AVADLLLTST VLPFSAIFEV LGYWAFGRVF CNIWAAVDV LCCTASIMGL CIISIDRYIG VSYPLRYPTI VTQRRGLMAL LCVWALSLVI SIGPLFGWRQ PAPEDETICQ I NEEPGYVL ...String:
APVNISKAIL LGVILGGLIL FGVLGNILVI LSVACHRHLH SVTHYYIVNL AVADLLLTST VLPFSAIFEV LGYWAFGRVF CNIWAAVDV LCCTASIMGL CIISIDRYIG VSYPLRYPTI VTQRRGLMAL LCVWALSLVI SIGPLFGWRQ PAPEDETICQ I NEEPGYVL FSALGSFYLP LAIILVMYCR VYVVAKRESR GLKSGLKTDK SDSEQVTLRI HRKNAPAGGS GMASAKTKTH FS VRLLKFS REKKAAKTLG IVVGCFVLCW LPFFLVMPIG SFFPDFKPSE TVFKIVFWLG YLNSCINPII YPCSSQEFKK AFQ NVL

UniProtKB: Alpha-1A adrenergic receptor

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Macromolecule #2: Silodosin

MacromoleculeName: Silodosin / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EMV
Molecular weightTheoretical: 495.534 Da

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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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 1.7 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 3759439
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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