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- PDB-7xrr: Crystal structure of the human OX2R bound to the insomnia drug le... -

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Basic information

Entry
Database: PDB / ID: 7xrr
TitleCrystal structure of the human OX2R bound to the insomnia drug lemborexant.
ComponentsOrexin receptor type 2
KeywordsMEMBRANE PROTEIN / GPCR / insomnia drug
Function / homology
Function and homology information


regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / feeding behavior / locomotion / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus ...regulation of circadian sleep/wake cycle, wakefulness / circadian sleep/wake cycle process / orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide receptor activity / feeding behavior / locomotion / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / peptide binding / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / synapse / plasma membrane
Similarity search - Function
Orexin receptor 2 / Orexin receptor type 2 / Orexin receptor 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
Chem-NRK / Orexin receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.89 Å
AuthorsAsada, H. / Im, D. / Iwata, S.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21am0101079 Japan
Japan Agency for Medical Research and Development (AMED)JP21am0101070 Japan
Japan Agency for Medical Research and Development (AMED)JP21am0101083 Japan
CitationJournal: Structure / Year: 2022
Title: Molecular basis for anti-insomnia drug design from structure of lemborexant-bound orexin 2 receptor.
Authors: Asada, H. / Im, D. / Hotta, Y. / Yasuda, S. / Murata, T. / Suno, R. / Iwata, S.
History
DepositionMay 11, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 23, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 14, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Orexin receptor type 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9722
Polymers39,5621
Non-polymers4101
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16820 Å2
Unit cell
Length a, b, c (Å)49.590, 90.230, 112.320
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Orexin receptor type 2 / Ox-2-R / Ox2-R / Ox2R / Hypocretin receptor type 2


Mass: 39561.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCRTR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43614
#2: Chemical ChemComp-NRK / (1~{R},2~{S})-2-[(2,4-dimethylpyrimidin-5-yl)oxymethyl]-~{N}-(5-fluoranylpyridin-2-yl)-2-(3-fluorophenyl)cyclopropane-1-carboxamide


Mass: 410.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20F2N4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antagonist*YM
Has ligand of interestY

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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: 2.8 Å3/Da / Density % sol: 56.07 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase / pH: 6
Details: 21-28% PEG300, 80-120 mM Potassium citrate tribasic monohydrate, 0.1 M MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.89→40.53 Å / Num. obs: 11873 / % possible obs: 99.9 % / Redundancy: 59.799 % / Biso Wilson estimate: 72.1 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.713 / Rrim(I) all: 0.718 / Χ2: 1.332 / Net I/σ(I): 11.93 / Num. measured all: 709999 / Scaling rejects: 376
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.89-3.0757.8734.9860.81111752193119310.495.029100
3.07-3.2861.763.4331.52106597172617260.73.46100
3.28-3.5461.8442.7852.87102166165216520.8892.808100
3.54-3.8860.2341.4385.8191375151715170.961.45100
3.88-4.3357.3320.62612.0378659137213720.9880.631100
4.33-5.0162.5840.35421.4579231126612660.9950.357100
5.01-6.1361.1230.30622.2964179105010500.9970.308100
6.13-8.6755.3510.19632.06470488508500.9990.197100
8.67-40.5356.9590.14358.01289925155090.9990.14498.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQC

5wqc


Resolution: 2.89→40.53 Å / SU ML: 0.47 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 28.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.287 1182 10 %
Rwork0.2748 10637 -
obs0.2761 11819 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 176.67 Å2 / Biso mean: 74.0451 Å2 / Biso min: 39.67 Å2
Refinement stepCycle: final / Resolution: 2.89→40.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2520 0 30 0 2550
Biso mean--59.7 --
Num. residues----309
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.89-3.020.42941440.407612931437
3.02-3.180.37331440.346213061450
3.18-3.380.2861450.313913011446
3.38-3.640.33831480.293413191467
3.64-4.010.28441440.277813101454
4.01-4.590.26781490.272813381487
4.59-5.780.30651500.254213421492
5.78-40.530.21761580.230414281586
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.96050.46590.97643.9512.43313.0234-0.04080.1620.0099-0.6295-0.44610.4762-0.3328-0.31630.60950.51910.0287-0.01570.6308-0.09560.6144-7.09269.046827.3731
22.18491.19981.8493.27332.29996.6563-0.1319-0.15470.2122-0.1515-0.22650.0345-0.1737-0.33390.36090.24150.03220.03720.4032-0.03460.37135.82914.652138.7322
32.93780.9398-0.19486.39073.16023.6120.0820.3812-0.2808-0.0067-0.18130.4120.5955-0.33970.11540.25150.0684-0.00950.5313-0.12150.55975.2114-0.412430.5058
45.9992.18825.60852.4983.18518.8691-0.5519-0.4371.5774-0.34410.2295-0.1569-0.2533-0.4971-0.060.9143-0.08120.11420.8868-0.20370.64732.5705-10.79985.7107
51.5731-1.7002-1.5715.50233.74065.9148-0.2386-0.1979-0.45650.9082-0.13670.34361.01860.07140.13210.4277-0.17460.00480.5649-0.10480.5716-3.3271-2.814538.1481
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 107 through 218 )A107 - 218
2X-RAY DIFFRACTION2chain 'A' and (resid 219 through 328 )A219 - 328
3X-RAY DIFFRACTION3chain 'A' and (resid 329 through 384 )A329 - 384
4X-RAY DIFFRACTION4chain 'A' and (resid 37 through 53 )A37 - 53
5X-RAY DIFFRACTION5chain 'A' and (resid 54 through 106 )A54 - 106

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