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- PDB-9ijd: Carazolol-activated human beta3 adrenergic receptor -

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Basic information

Entry
Database: PDB / ID: 9ijd
TitleCarazolol-activated human beta3 adrenergic receptor
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Beta-3 adrenergic receptor
  • Camelid antibody VHH fragment
  • Single-chain Fv16
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Complex / beta3AR / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / energy reserve metabolic process / corticotropin-releasing hormone receptor 1 binding / G-protein activation / Activation of the phototransduction cascade ...beta-3 adrenergic receptor binding / beta3-adrenergic receptor activity / beta-adrenergic receptor activity / epinephrine binding / sensory perception of chemical stimulus / mu-type opioid receptor binding / energy reserve metabolic process / corticotropin-releasing hormone receptor 1 binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / norepinephrine binding / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / Adrenoceptors / beta-2 adrenergic receptor binding / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / negative regulation of multicellular organism growth / photoreceptor outer segment membrane / G alpha (q) signalling events / G alpha (i) signalling events / spectrin binding / eating behavior / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / diet induced thermogenesis / alkylglycerophosphoethanolamine phosphodiesterase activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / photoreceptor outer segment / D1 dopamine receptor binding / brown fat cell differentiation / adenylate cyclase-activating adrenergic receptor signaling pathway / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / photoreceptor inner segment / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / response to cold / generation of precursor metabolites and energy / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / positive regulation of cold-induced thermogenesis / cell body / GTPase binding / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / carbohydrate metabolic process / cell population proliferation / receptor complex / positive regulation of MAPK cascade
Similarity search - Function
Beta 3 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ...Beta 3 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-CAU / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Beta-3 adrenergic receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Lama glama (llama)
Homo sapiens (human)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsZheng, S. / Zhang, S. / Dai, S. / Chen, K. / Gao, K. / Lin, B. / Liu, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122041 China
CitationJournal: Chempluschem / Year: 2024
Title: Molecular Mechanism of the βAR Agonist Activity of a β-Blocker.
Authors: Shuang Zheng / Shuhao Zhang / Shengjie Dai / Kai Chen / Kaixuan Gao / Xiaoou Sun / Bin Lin / Xiangyu Liu /
Abstract: Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors ...Development of subtype-selective drugs for G protein-coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β-adrenergic receptors (βARs). The βAR agonists show promise for treating the overactive bladder or preterm birth, but their potential is hindered by off-target activation of βAR and βAR. Interestingly, several β-blockers, which are antagonists of the βARs and βARs, have been reported to exhibit agonist activity at the βAR. However, the molecular mechanism remains elusive. Understanding the underlying mechanism should facilitate the development of βAR agonists with improved selectivity and reduced off-target effects. In this work, we determined the structures of human βAR in complex with the endogenous agonist epinephrine or with a synthetic βAR agonist carazolol, which is also a high-affinity β-blocker. Structure comparison, mutagenesis studies and molecular dynamics simulations revealed that the differences on the flexibility of D directly contribute to carazolol's distinct activities as an antagonist for the βAR and an agonist for the βAR. The process is also indirectly influenced by the extracellular loops (ECL), especially ECL1. Taken together, these results provide key guidance for development of selective βAR agonists, paving the way for new therapeutic opportunities.
History
DepositionJun 22, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 21, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Dec 25, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.title ..._citation.journal_volume / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
N: Camelid antibody VHH fragment
D: Single-chain Fv16
R: Beta-3 adrenergic receptor
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)161,5037
Polymers161,2056
Non-polymers2981
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BAC

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37413.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#5: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 43320.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNAS, GNAS1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P04896
#6: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 5731.619 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212

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Antibody , 2 types, 2 molecules ND

#2: Antibody Camelid antibody VHH fragment


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Antibody Single-chain Fv16


Mass: 26206.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)

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Protein / Non-polymers , 2 types, 2 molecules R

#4: Protein Beta-3 adrenergic receptor / Beta-3 adrenoreceptor / Beta-3 adrenoceptor


Mass: 34647.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRB3, ADRB3R, B3AR / Production host: Homo sapiens (human) / References: UniProt: P13945
#7: Chemical ChemComp-CAU / (2S)-1-(9H-Carbazol-4-yloxy)-3-(isopropylamino)propan-2-ol / (S)-Carazolol


Mass: 298.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22N2O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

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

ComponentName: Carazolol bounded human beta3 adrenergic receptor-Gs protein complex with Gbeta, Ggamma, Nb35 and scFv16
Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1623386 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0089569
ELECTRON MICROSCOPYf_angle_d0.91713002
ELECTRON MICROSCOPYf_dihedral_angle_d4.1041337
ELECTRON MICROSCOPYf_chiral_restr0.0421486
ELECTRON MICROSCOPYf_plane_restr0.0051653

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