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- PDB-6to7: Crystal structure of the Orexin-1 receptor in complex with suvore... -

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Basic information

Entry
Database: PDB / ID: 6to7
TitleCrystal structure of the Orexin-1 receptor in complex with suvorexant at 2.29 A resolution
ComponentsOrexin receptor type 1
KeywordsMEMBRANE PROTEIN / 7TM / GPCR
Function / homology
Function and homology information


orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / feeding behavior / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / G protein-coupled receptor activity / peptide binding / chemical synaptic transmission ...orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / feeding behavior / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / G protein-coupled receptor activity / peptide binding / chemical synaptic transmission / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / synapse / plasma membrane
Similarity search - Function
Orexin/Hypocretin receptor type 1 / 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
CITRIC ACID / Chem-PGW / Chem-SUV / Orexin/Hypocretin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.26 Å
AuthorsRappas, M. / Ali, A. / Bennett, K.A. / Brown, J.D. / Bucknell, S.J. / Congreve, M. / Cooke, R.M. / Cseke, G. / de Graaf, C. / Dore, A.S. ...Rappas, M. / Ali, A. / Bennett, K.A. / Brown, J.D. / Bucknell, S.J. / Congreve, M. / Cooke, R.M. / Cseke, G. / de Graaf, C. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / Mason, J.S. / Mould, R. / Patel, J.C. / Tehan, B.G. / Weir, M. / Christopher, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA)R01DA039553 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Comparison of Orexin 1 and Orexin 2 Ligand Binding Modes Using X-ray Crystallography and Computational Analysis.
Authors: Rappas, M. / Ali, A.A.E. / Bennett, K.A. / Brown, J.D. / Bucknell, S.J. / Congreve, M. / Cooke, R.M. / Cseke, G. / de Graaf, C. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / ...Authors: Rappas, M. / Ali, A.A.E. / Bennett, K.A. / Brown, J.D. / Bucknell, S.J. / Congreve, M. / Cooke, R.M. / Cseke, G. / de Graaf, C. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / Mason, J.S. / Mould, R. / Patel, J.C. / Tehan, B.G. / Weir, M. / Christopher, J.A.
History
DepositionDec 11, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 1, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation.year / _citation_author.name
Revision 1.2Mar 11, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jul 29, 2020Group: Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Oct 16, 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

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Assembly

Deposited unit
A: Orexin receptor type 1
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,94356
Polymers76,2662
Non-polymers16,67854
Water2,666148
1
A: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,52828
Polymers38,1331
Non-polymers8,39527
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,41628
Polymers38,1331
Non-polymers8,28327
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.9, 158.47, 183.62
Angle α, β, γ (deg.)90, 95.31, 90
Int Tables number5
Space group name H-MI121

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Components

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Protein / Sugars , 2 types, 45 molecules AB

#1: Protein Orexin receptor type 1 / Ox1R / Hypocretin receptor type 1


Mass: 38132.852 Da / Num. of mol.: 2
Mutation: E46A I85L V95A R162L N194A L198A Y211A L304V C339A C375W C376W
Source method: isolated from a genetically manipulated source
Details: Suvorexant bound / Source: (gene. exp.) Homo sapiens (human) / Gene: HCRTR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43613
#5: Sugar...
ChemComp-SOG / octyl 1-thio-beta-D-glucopyranoside / 2-HYDROXYMETHYL-6-OCTYLSULFANYL-TETRAHYDRO-PYRAN-3,4,5-TRIOL / 1-S-OCTYL-BETA-D-THIOGLUCOSIDE / octyl 1-thio-beta-D-glucoside / octyl 1-thio-D-glucoside / octyl 1-thio-glucoside


Type: D-saccharide / Mass: 308.434 Da / Num. of mol.: 43
Source method: isolated from a genetically manipulated source
Formula: C14H28O5S / Comment: detergent*YM

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Non-polymers , 6 types, 159 molecules

#2: Chemical ChemComp-SUV / [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone / suvorexant


Mass: 450.921 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23ClN6O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antagonist*YM
#3: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#6: Chemical ChemComp-PGW / (1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl (9Z)-octadec-9-enoate / 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-[Phospho-(1-glycerol)] / PHOSPHATIDYLGLYCEROL


Mass: 749.007 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C40H77O10P / Comment: phospholipid*YM
#7: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 148 / Source method: isolated from a natural source / Formula: H2O

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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

Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 6.2
Details: 0.1M TRISODIUM CITRATE 50mM SODIUM CHLORIDE 50mM LITHIUM SULPHATE 15-34% PEG400
PH range: 3.0-6.5 / Temp details: Stable

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Stable / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 17, 2012
RadiationMonochromator: SI (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.29→44.39 Å / Num. obs: 45066 / % possible obs: 92.9 % / Redundancy: 5.4 % / CC1/2: 0.985 / Rpim(I) all: 0.14 / Net I/σ(I): 4.8
Reflection shellResolution: 2.29→2.48 Å / Num. unique obs: 902 / CC1/2: 0.397 / % possible all: 52.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DJH

4djh


Resolution: 2.26→44.38 Å / Cor.coef. Fo:Fc: 0.909 / Cor.coef. Fo:Fc free: 0.875 / SU R Cruickshank DPI: 0.258 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.247 / SU Rfree Blow DPI: 0.198 / SU Rfree Cruickshank DPI: 0.203
RfactorNum. reflection% reflectionSelection details
Rfree0.211 2243 -RANDOM
Rwork0.186 ---
obs0.187 45066 58.8 %-
Displacement parametersBiso mean: 46.25 Å2
Baniso -1Baniso -2Baniso -3
1--3.6696 Å20 Å22.5557 Å2
2---1.5257 Å20 Å2
3---5.1952 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.26→44.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4828 0 785 148 5761
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015807HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.037773HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2250SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes815HARMONIC5
X-RAY DIFFRACTIONt_it5807HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_chiral_improper_torsion784SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6550SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion17.27
LS refinement shellResolution: 2.26→2.48 Å
RfactorNum. reflection% reflection
Rfree0.2699 48 -
Rwork0.2064 --
obs0.2094 902 4.96 %
Refinement TLS params.

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)
11.6544-0.1267-0.58391.98480.24991.7856-0.11410.29880.1930.29880.05260.1480.1930.1480.0615-0.11460.0540.0244-0.17020.0008-0.0934-16.2229-56.5069-24.2909
21.98690.0017-0.09251.4472-0.06060.8658-0.0071-0.0066-0.0854-0.00660.053-0.0504-0.0854-0.0504-0.0458-0.1856-0.01030.0251-0.10780.0812-0.041-27.3114-29.8447-40.5171
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|45 - 377}
2X-RAY DIFFRACTION2{B|30 - 383}

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