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- PDB-6mxt: Crystal structure of human beta2 adrenergic receptor bound to sal... -

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Basic information

Entry
Database: PDB / ID: 6mxt
TitleCrystal structure of human beta2 adrenergic receptor bound to salmeterol and Nb71
Components
  • Endolysin, Beta-2 adrenergic receptor chimeraLysin
  • nanobody Nb71
KeywordsSIGNALING PROTEIN/HORMONE / G protein-coupled receptor / adrenergic receptor / asthma drug / active conformation / nanobody / SIGNALING PROTEIN-HORMONE complex / membrane protein
Function / homology
Function and homology information


desensitization of G protein-coupled receptor signaling pathway by arrestin / beta2-adrenergic receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / positive regulation of mini excitatory postsynaptic potential / positive regulation of cAMP-dependent protein kinase activity / norepinephrine binding / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity ...desensitization of G protein-coupled receptor signaling pathway by arrestin / beta2-adrenergic receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / positive regulation of mini excitatory postsynaptic potential / positive regulation of cAMP-dependent protein kinase activity / norepinephrine binding / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / response to psychosocial stress / negative regulation of multicellular organism growth / adrenergic receptor signaling pathway / endosome to lysosome transport / neuronal dense core vesicle / diet induced thermogenesis / positive regulation of protein kinase A signaling / adenylate cyclase binding / smooth muscle contraction / potassium channel regulator activity / positive regulation of bone mineralization / brown fat cell differentiation / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / bone resorption / viral release from host cell by cytolysis / activation of adenylate cyclase activity / response to cold / receptor-mediated endocytosis / peptidoglycan catabolic process / clathrin-coated endocytic vesicle membrane / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of protein serine/threonine kinase activity / cellular response to amyloid-beta / cell wall macromolecule catabolic process / Cargo recognition for clathrin-mediated endocytosis / lysozyme / Clathrin-mediated endocytosis / lysozyme activity / positive regulation of cold-induced thermogenesis / amyloid-beta binding / G alpha (s) signalling events / host cell cytoplasm / transcription by RNA polymerase II / positive regulation of MAPK cascade / lysosome / cell surface receptor signaling pathway / early endosome / receptor complex / endosome membrane / Ub-specific processing proteases / endosome / defense response to bacterium / apical plasma membrane / protein-containing complex binding / Golgi apparatus / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Beta 2 adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Beta 2 adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / 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) / Lysozyme-like domain superfamily
Similarity search - Domain/homology
HEPTANE-1,2,3-TRIOL / salmeterol / NICKEL (II) ION / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Endolysin / Endolysin / Beta-2 adrenergic receptor
Similarity search - Component
Biological speciesEnterobacteria phage T4 (virus)
Homo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95934213525 Å
AuthorsMasureel, M. / Zou, Y. / Picard, L.P. / van der Westhuizen, E. / Mahoney, J.P. / Rodrigues, J.P.G.L.M. / Mildorf, T.J. / Dror, R.O. / Shaw, D.E. / Bouvier, M. ...Masureel, M. / Zou, Y. / Picard, L.P. / van der Westhuizen, E. / Mahoney, J.P. / Rodrigues, J.P.G.L.M. / Mildorf, T.J. / Dror, R.O. / Shaw, D.E. / Bouvier, M. / Pardon, E. / Steyaert, J. / Sunahara, R.K. / Weis, W.I. / Zhang, C. / Kobilka, B.K.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5U19GM106990-05 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM128641-01 United States
CitationJournal: Nat. Chem. Biol. / Year: 2018
Title: Structural insights into binding specificity, efficacy and bias of a beta2AR partial agonist.
Authors: Masureel, M. / Zou, Y. / Picard, L.P. / van der Westhuizen, E. / Mahoney, J.P. / Rodrigues, J.P.G.L.M. / Mildorf, T.J. / Dror, R.O. / Shaw, D.E. / Bouvier, M. / Pardon, E. / Steyaert, J. / ...Authors: Masureel, M. / Zou, Y. / Picard, L.P. / van der Westhuizen, E. / Mahoney, J.P. / Rodrigues, J.P.G.L.M. / Mildorf, T.J. / Dror, R.O. / Shaw, D.E. / Bouvier, M. / Pardon, E. / Steyaert, J. / Sunahara, R.K. / Weis, W.I. / Zhang, C. / Kobilka, B.K.
History
DepositionOct 31, 2018Deposition site: RCSB / Processing site: RCSB
SupersessionNov 14, 2018ID: 6CSY
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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.ptnr1_symmetry / _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 / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Endolysin, Beta-2 adrenergic receptor chimera
N: nanobody Nb71
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,73111
Polymers67,0022
Non-polymers1,7309
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-36 kcal/mol
Surface area26780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)178.682, 52.589, 125.917
Angle α, β, γ (deg.)90.0, 123.859, 90.0
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

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Protein / Antibody , 2 types, 2 molecules AN

#1: Protein Endolysin, Beta-2 adrenergic receptor chimera / Lysin / Lysis protein / Lysozyme / Muramidase / Beta-2 adrenoreceptor / Beta-2 adrenoceptor


Mass: 53528.066 Da / Num. of mol.: 1
Fragment: chimera of T4 lysozyme fused to human beta2 adrenergic receptor (UNP residues 29-234,263-365)
Mutation: M96T, M98T, N187E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Enterobacteria phage T4 (virus), (gene. exp.) Homo sapiens (human)
Gene: e, T4Tp126, ADRB2, ADRB2R, B2AR / Plasmid: pVL1392 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: D9IEF7, UniProt: P07550, UniProt: P00720*PLUS, lysozyme
#2: Antibody nanobody Nb71


Mass: 13473.763 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)

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Non-polymers , 8 types, 29 molecules

#3: Chemical ChemComp-K5Y / salmeterol / 2-(hydroxymethyl)-4-[(1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)hexyl]amino}ethyl]phenol / Salmeterol


Mass: 415.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H37NO4 / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ni
#6: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4
#7: Chemical ChemComp-HTO / HEPTANE-1,2,3-TRIOL


Mass: 148.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H16O3
#8: Chemical ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H34O2
#9: Chemical ChemComp-P33 / 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL / HEPTAETHYLENE GLYCOL / PEG330 / Polyethylene glycol


Mass: 326.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O8 / Comment: precipitant*YM
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 3.8 Å3/Da / Density % sol: 67.64 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase / pH: 7.5
Details: 31-34% PEG400, 100 mM HEPES, pH 7.5, 1% 1,2,3-heptanetriol

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 0.987 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Dec 18, 2012
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.95→30 Å / Num. obs: 18742 / % possible obs: 92.6 % / Redundancy: 3.3 % / Biso Wilson estimate: 52.7347764892 Å2 / Rmerge(I) obs: 0.167 / Net I/σ(I): 1.52
Reflection shellResolution: 2.95→3.09 Å / Rmerge(I) obs: 0.525 / Mean I/σ(I) obs: 1.52 / Num. unique obs: 1012 / Χ2: 7.5 / % possible all: 75

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Processing

Software
NameVersionClassification
HKL-20001.9_1692data collection
PHENIX1.9_1692refinement
PHASERphasing
Cootmodel building
SCALEPACKdata scaling
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 4GBR & 4LDE

4gbr

4lde


Resolution: 2.95934213525→28.5196106168 Å / SU ML: 0.402084390742 / Cross valid method: FREE R-VALUE / σ(F): 1.38231122584 / Phase error: 24.3772282005
RfactorNum. reflection% reflection
Rfree0.24486451981 1135 6.05591719133 %
Rwork0.204625198648 --
obs0.207099158562 18742 90.7558955983 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 53.7137652891 Å2
Refinement stepCycle: LAST / Resolution: 2.95934213525→28.5196106168 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4539 0 111 20 4670
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.001949980790854768
X-RAY DIFFRACTIONf_angle_d0.5707627610766443
X-RAY DIFFRACTIONf_chiral_restr0.0213092559887723
X-RAY DIFFRACTIONf_plane_restr0.00270009590516797
X-RAY DIFFRACTIONf_dihedral_angle_d11.72955989381731
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9593-3.09390.3385902513671070.2952837919271554X-RAY DIFFRACTION65.0607128868
3.0939-3.25680.3026209288811340.2799352545432127X-RAY DIFFRACTION89.085894405
3.2568-3.46050.3171605210181450.2579550973322234X-RAY DIFFRACTION93.0387172468
3.4605-3.72710.2520696961931490.2221268483532320X-RAY DIFFRACTION95.6976744186
3.7271-4.10120.2563665686691460.1997028631182327X-RAY DIFFRACTION96.2256809339
4.1012-4.69240.2115281182551500.1776583891152341X-RAY DIFFRACTION96.6252909232
4.6924-5.90330.2165169884771520.1824608738052347X-RAY DIFFRACTION96.2634822804
5.9033-28.52090.2082526205241520.1692108568852357X-RAY DIFFRACTION93.6543486376

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