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- PDB-6ps1: XFEL beta2 AR structure by ligand exchange from Alprenolol to Timolol. -

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Basic information

Entry
Database: PDB / ID: 6ps1
TitleXFEL beta2 AR structure by ligand exchange from Alprenolol to Timolol.
ComponentsFusion protein of Beta-2 adrenergic receptor and T4 lysozyme
KeywordsMEMBRANE PROTEIN / GPCR / COMPLEX-LCP method / SBDD / drug design / XFEL / LCP-SFX / Ligand Exchange / Alprenolol / Timolol / b2AR / beta2AR
Function / homology
Function and homology information


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 / positive regulation of AMPA receptor activity / norepinephrine binding / positive regulation of autophagosome maturation / heat generation / Adrenoceptors / activation of transmembrane receptor protein tyrosine kinase activity ...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 / positive regulation of AMPA receptor activity / norepinephrine binding / positive regulation of autophagosome maturation / heat generation / Adrenoceptors / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / negative regulation of multicellular organism growth / negative regulation of G protein-coupled receptor signaling pathway / response to psychosocial stress / endosome to lysosome transport / adrenergic receptor signaling pathway / diet induced thermogenesis / positive regulation of protein kinase A signaling / neuronal dense core vesicle / adenylate cyclase binding / smooth muscle contraction / bone resorption / 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 / viral release from host cell by cytolysis / response to cold / peptidoglycan catabolic process / receptor-mediated endocytosis / clathrin-coated endocytic vesicle membrane / positive regulation of protein serine/threonine kinase activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cellular response to amyloid-beta / cell wall macromolecule catabolic process / Cargo recognition for clathrin-mediated endocytosis / lysozyme / lysozyme activity / positive regulation of cold-induced thermogenesis / Clathrin-mediated endocytosis / amyloid-beta binding / G alpha (s) signalling events / host cell cytoplasm / transcription by RNA polymerase II / positive regulation of MAPK cascade / lysosome / early endosome / receptor complex / cell surface receptor signaling pathway / 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 / identical protein binding / membrane / nucleus / plasma membrane
Similarity search - Function
Beta 2 adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. ...Beta 2 adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / 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
CHOLESTEROL / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Chem-TIM / Endolysin / Beta-2 adrenergic receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / FREE ELECTRON LASER / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.2 Å
AuthorsIshchenko, A. / Stauch, B. / Han, G.W. / Batyuk, A. / Shiriaeva, A. / Li, C. / Zatsepin, N.A. / Weierstall, U. / Liu, W. / Nango, E. ...Ishchenko, A. / Stauch, B. / Han, G.W. / Batyuk, A. / Shiriaeva, A. / Li, C. / Zatsepin, N.A. / Weierstall, U. / Liu, W. / Nango, E. / Nakane, T. / Tanaka, R. / Tono, K. / Joti, Y. / Iwata, S. / Moraes, I. / Gati, C. / Cherezov, C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM127086 United States
CitationJournal: Iucrj / Year: 2019
Title: Toward G protein-coupled receptor structure-based drug design using X-ray lasers.
Authors: Ishchenko, A. / Stauch, B. / Han, G.W. / Batyuk, A. / Shiriaeva, A. / Li, C. / Zatsepin, N. / Weierstall, U. / Liu, W. / Nango, E. / Nakane, T. / Tanaka, R. / Tono, K. / Joti, Y. / Iwata, S. ...Authors: Ishchenko, A. / Stauch, B. / Han, G.W. / Batyuk, A. / Shiriaeva, A. / Li, C. / Zatsepin, N. / Weierstall, U. / Liu, W. / Nango, E. / Nakane, T. / Tanaka, R. / Tono, K. / Joti, Y. / Iwata, S. / Moraes, I. / Gati, C. / Cherezov, V.
History
DepositionJul 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2019Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fusion protein of Beta-2 adrenergic receptor and T4 lysozyme
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,7619
Polymers57,7741
Non-polymers1,9878
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.730, 76.330, 172.000
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
DetailsAUTHORS STATE THAT THE BIOLOGICAL UNIT IS UNKNOWN

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Fusion protein of Beta-2 adrenergic receptor and T4 lysozyme / Beta-2 adrenoreceptor / Beta-2 adrenoceptor / Lysis protein / Lysozyme / Muramidase


Mass: 57774.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: ADRB2, ADRB2R, B2AR, e, T4Tp126 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550, UniProt: D9IEF7

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Non-polymers , 5 types, 8 molecules

#2: Chemical ChemComp-TIM / (2S)-1-(tert-butylamino)-3-[(4-morpholin-4-yl-1,2,5-thiadiazol-3-yl)oxy]propan-2-ol / Timolol maleate


Mass: 316.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H24N4O3S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#5: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H34O2

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.37 Å3/Da / Density % sol: 48.12 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.1 M HEPES pH 7.0, 0.1 M Ammonium Sulfate, 30% PEG 400, 2 mM of target ligand Timolol

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: Y
Diffraction sourceSource: FREE ELECTRON LASER / Site: SLAC LCLS / Beamline: CXI / Wavelength: 1.33 Å
DetectorType: CS-PAD CXI-1 / Detector: PIXEL / Date: Nov 3, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.33 Å / Relative weight: 1
ReflectionResolution: 3.2→30.9 Å / Num. obs: 9646 / % possible obs: 100 % / Redundancy: 670.8 % / CC1/2: 0.995 / R split: 0.172 / Net I/σ(I): 5.7
Reflection shellResolution: 3.2→3.58 Å / Num. unique obs: 2666 / CC1/2: 0.267 / R split: 1.884
Serial crystallography measurementCollection time total: 3.48 hours / Focal spot size: 1.5 µm2 / Pulse duration: 42 fsec. / Pulse photon energy: 9.5 keV / XFEL pulse repetition rate: 120 Hz
Serial crystallography sample deliveryMethod: injection
Serial crystallography sample delivery injectionFlow rate: 0.2 µL/min / Injector diameter: 50 µm
Serial crystallography data reductionCrystal hits: 238986 / Frames indexed: 59814 / Frames total: 1503057

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHASERphasing
BUSTER2.10.2refinement
PDB_EXTRACT3.25data extraction
CrystFELdata reduction
CrystFELdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3d4s

3d4s


Resolution: 3.2→30.86 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.929 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.509
RfactorNum. reflection% reflectionSelection details
Rfree0.264 476 4.98 %RANDOM
Rwork0.229 ---
obs0.23 9559 99.5 %-
Displacement parametersBiso max: 230.51 Å2 / Biso mean: 135.84 Å2 / Biso min: 96.57 Å2
Baniso -1Baniso -2Baniso -3
1--11.9195 Å20 Å20 Å2
2--9.9372 Å20 Å2
3---1.9823 Å2
Refine analyzeLuzzati coordinate error obs: 0.64 Å
Refinement stepCycle: final / Resolution: 3.2→30.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3410 0 107 0 3517
Biso mean--158.19 --
Num. residues----442
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1605SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes66HARMONIC2
X-RAY DIFFRACTIONt_gen_planes524HARMONIC5
X-RAY DIFFRACTIONt_it3599HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion497SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4280SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3599HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg4914HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion1.91
X-RAY DIFFRACTIONt_other_torsion2.85
LS refinement shellResolution: 3.2→3.58 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.278 131 5.03 %
Rwork0.256 2472 -
all0.257 2603 -
obs--98.41 %
Refinement TLS params.Method: refined / Origin x: 8.4081 Å / Origin y: 3.4338 Å / Origin z: 26.2701 Å
111213212223313233
T0.0916 Å20.0015 Å2-0.0009 Å2--0.0826 Å20.0441 Å2---0.3232 Å2
L0.7983 °2-0.0552 °2-0.8159 °2-0.7525 °20.3713 °2--3.3006 °2
S0.0191 Å °0.0168 Å °0.0253 Å °0.1094 Å °0.0201 Å °-0.0304 Å °-0.1376 Å °0.0177 Å °-0.0392 Å °
Refinement TLS groupSelection details: { A|* }

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