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- PDB-6ibl: ACTIVATED TURKEY BETA1 ADRENOCEPTOR WITH BOUND AGONIST FORMOTEROL... -

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Basic information

Entry
Database: PDB / ID: 6ibl
TitleACTIVATED TURKEY BETA1 ADRENOCEPTOR WITH BOUND AGONIST FORMOTEROL AND NANOBODY Nb80
Components
  • Camelid antibody fragment Nb80
  • Thioredoxin 1,Beta-1 adrenergic receptor
KeywordsIMMUNE SYSTEM / Beta1 Adrenoceptor / Activated / Agonist / Nanobody
Function / homology
Function and homology information


beta1-adrenergic receptor activity / positive regulation of heart rate by epinephrine-norepinephrine / regulation of circadian sleep/wake cycle, sleep / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / DNA polymerase processivity factor activity / protein-disulfide reductase activity / adenylate cyclase-activating adrenergic receptor signaling pathway / cell redox homeostasis / early endosome / identical protein binding ...beta1-adrenergic receptor activity / positive regulation of heart rate by epinephrine-norepinephrine / regulation of circadian sleep/wake cycle, sleep / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / DNA polymerase processivity factor activity / protein-disulfide reductase activity / adenylate cyclase-activating adrenergic receptor signaling pathway / cell redox homeostasis / early endosome / identical protein binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Beta 1 adrenoceptor / Thioredoxin / Adrenoceptor family / Thioredoxin / Thioredoxin, conserved site / Thioredoxin family active site. / Thioredoxin domain profile. / Thioredoxin domain / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. ...Beta 1 adrenoceptor / Thioredoxin / Adrenoceptor family / Thioredoxin / Thioredoxin, conserved site / Thioredoxin family active site. / Thioredoxin domain profile. / Thioredoxin domain / 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) / Thioredoxin-like superfamily
Similarity search - Domain/homology
Chem-H98 / Beta-1 adrenergic receptor / Thioredoxin 1
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Meleagris gallopavo (turkey)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWarne, T. / Edwards, P.C. / Dore, A.S. / Leslie, A.G.W. / Tate, C.G.
Citation
Journal: Nature / Year: 2020
Title: Molecular basis of β-arrestin coupling to formoterol-bound β-adrenoceptor.
Authors: Yang Lee / Tony Warne / Rony Nehmé / Shubhi Pandey / Hemlata Dwivedi-Agnihotri / Madhu Chaturvedi / Patricia C Edwards / Javier García-Nafría / Andrew G W Leslie / Arun K Shukla / Christopher G Tate /
Abstract: The β-adrenoceptor (βAR) is a G-protein-coupled receptor (GPCR) that couples to the heterotrimeric G protein G. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of ...The β-adrenoceptor (βAR) is a G-protein-coupled receptor (GPCR) that couples to the heterotrimeric G protein G. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces G and induces signalling through the MAP kinase pathway. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the βAR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol, and the crystal structure of formoterol-bound βAR coupled to the G-protein-mimetic nanobody Nb80. βarr1 couples to βAR in a manner distinct to that of G coupling to βAR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of G. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin. βAR coupled to βarr1 shows considerable differences in structure compared with βAR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of βAR, and find that formoterol has a lower affinity for the βAR-βarr1 complex than for the βAR-G complex. The structural differences between these complexes of βAR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors.
#1: Journal: Biorxiv / Year: 2018
Title: Molecular basis for high affinity agonist binding in GPCRs
Authors: Warne, T. / Edwards, P.C. / Dore, A.S. / Leslie, A.G.W. / Tate, C.G.
History
DepositionNov 30, 2018Deposition site: PDBE / Processing site: PDBE
SupersessionJan 9, 2019ID: 6H7K
Revision 1.0Jan 9, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.year
Revision 1.2Jul 8, 2020Group: Database references / Category: citation / citation_author
Revision 1.3Aug 12, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Revision 1.4Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model
Item: _citation.journal_id_ISSN / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thioredoxin 1,Beta-1 adrenergic receptor
C: Camelid antibody fragment Nb80
B: Thioredoxin 1,Beta-1 adrenergic receptor
D: Camelid antibody fragment Nb80
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,39416
Polymers119,6234
Non-polymers3,77112
Water52229
1
A: Thioredoxin 1,Beta-1 adrenergic receptor
C: Camelid antibody fragment Nb80
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0769
Polymers59,8112
Non-polymers2,2657
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2550 Å2
ΔGint-25 kcal/mol
Surface area26070 Å2
MethodPISA
2
B: Thioredoxin 1,Beta-1 adrenergic receptor
D: Camelid antibody fragment Nb80
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3177
Polymers59,8112
Non-polymers1,5065
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-26 kcal/mol
Surface area25610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.650, 121.120, 129.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11E
21F
12A
22B
13C
23D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010E3 - 108
2010F3 - 108
1020E41 - 358
2020F41 - 358
1030C2 - 119
2030D2 - 119

NCS ensembles :
ID
1
2
3

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Components

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Protein / Antibody , 2 types, 4 molecules ABCD

#1: Protein Thioredoxin 1,Beta-1 adrenergic receptor / Trx-1 / Beta-1 adrenoreceptor / Beta-T


Mass: 46769.094 Da / Num. of mol.: 2 / Mutation: C32S,C35S,C32S,C35S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (strain K12) (bacteria), (gene. exp.) Meleagris gallopavo (turkey)
Strain: K12 / Gene: trxA, fipA, tsnC, b3781, JW5856, ADRB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0AA25, UniProt: P07700
#2: Antibody Camelid antibody fragment Nb80


Mass: 13042.373 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: pET-26b(+) / Production host: Escherichia coli (E. coli)

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Non-polymers , 4 types, 41 molecules

#3: Chemical ChemComp-H98 / ~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino]-1-oxidanyl-ethyl]-2-oxidanyl-phenyl]methanamide


Mass: 344.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24N2O4 / Comment: agonist*YM
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical
ChemComp-2CV / HEGA-10


Mass: 379.489 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C18H37NO7 / Comment: detergent*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 29 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.02 Å3/Da / Density % sol: 69.41 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.1 M Hepes-NaOH pH7.5 and 21-24% PEG1500

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 X 2M / Detector: PIXEL / Date: Dec 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 2.7→88.57 Å / Num. obs: 50611 / % possible obs: 99 % / Redundancy: 4.6 % / Net I/σ(I): 6.6
Reflection shellResolution: 2.7→2.79 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2H6X, 3P0G

2h6x

3p0g


Resolution: 2.7→44.32 Å / Cor.coef. Fo:Fc: 0.856 / Cor.coef. Fo:Fc free: 0.786 / SU B: 16.666 / SU ML: 0.326 / Cross valid method: THROUGHOUT / ESU R Free: 0.464 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27659 1570 4.9 %RANDOM
Rwork0.23953 ---
obs0.24135 30378 62.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 66.667 Å2
Baniso -1Baniso -2Baniso -3
1--2.21 Å2-0 Å20 Å2
2--1.34 Å2-0 Å2
3---0.88 Å2
Refinement stepCycle: 1 / Resolution: 2.7→44.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7984 0 258 29 8271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0138421
X-RAY DIFFRACTIONr_bond_other_d0.0020.0178079
X-RAY DIFFRACTIONr_angle_refined_deg1.5411.63411410
X-RAY DIFFRACTIONr_angle_other_deg1.1221.56718656
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.22851020
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.64121.524374
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.098151356
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6541546
X-RAY DIFFRACTIONr_chiral_restr0.0670.21130
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029127
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021791
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.3917.0164101
X-RAY DIFFRACTIONr_mcbond_other4.3887.0154100
X-RAY DIFFRACTIONr_mcangle_it7.17810.5135114
X-RAY DIFFRACTIONr_mcangle_other7.17710.5135115
X-RAY DIFFRACTIONr_scbond_it4.0857.3754320
X-RAY DIFFRACTIONr_scbond_other4.0847.3754321
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.84910.9046297
X-RAY DIFFRACTIONr_long_range_B_refined10.43578.8338859
X-RAY DIFFRACTIONr_long_range_B_other10.43478.8348860
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A27330.12
12B27330.12
21A98340.06
22B98340.06
31C37540.05
32D37540.05
LS refinement shellResolution: 2.705→2.775 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.372 5 -
Rwork0.313 98 -
obs--2.78 %

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