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- PDB-6tq4: Crystal structure of the Orexin-1 receptor in complex with Compound 16 -

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Basic information

Entry
Database: PDB / ID: 6tq4
TitleCrystal structure of the Orexin-1 receptor in complex with Compound 16
ComponentsOrexin receptor type 1Hypocretin (orexin) receptor 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
Chem-NV8 / Chem-PGW / Orexin/Hypocretin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.299 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 16, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)90,16224
Polymers83,4522
Non-polymers6,71022
Water75742
1
A: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,55514
Polymers41,7261
Non-polymers3,82913
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,60710
Polymers41,7261
Non-polymers2,8819
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.339, 145.892, 71.341
Angle α, β, γ (deg.)90.000, 112.330, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Sugars , 2 types, 15 molecules AB

#1: Protein Orexin receptor type 1 / Hypocretin (orexin) receptor 1 / Ox1R / Hypocretin receptor type 1


Mass: 41725.891 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: Compound 16 bound in the orthosteric site / 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 / N-Octyl beta-D-thioglucopyranoside


Type: D-saccharide / Mass: 308.434 Da / Num. of mol.: 13
Source method: isolated from a genetically manipulated source
Formula: C14H28O5S / Comment: detergent*YM

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Non-polymers , 5 types, 51 molecules

#2: Chemical ChemComp-NV8 / 2-[1-(phenylsulfonyl)-1,8-diazaspiro[4.5]decan-8-yl]-1,3-benzoxazole


Mass: 397.491 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23N3O3S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: 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 / Phosphatidylglycerol


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


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.75 Å3/Da / Density % sol: 67.16 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 4.8
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 6M / Detector: PIXEL / Date: Oct 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.29→34.693 Å / Num. obs: 38396 / % possible obs: 77.11 % / Redundancy: 3.5 % / CC1/2: 0.999 / Net I/σ(I): 13.4
Reflection shellResolution: 2.29→2.35 Å / Num. unique obs: 752 / CC1/2: 0.46

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6TO7

6to7


Resolution: 2.299→34.693 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 30.86
RfactorNum. reflection% reflection
Rfree0.2362 1896 4.94 %
Rwork0.2091 --
obs0.2105 38396 77.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 189.9 Å2 / Biso mean: 83.7506 Å2 / Biso min: 36.7 Å2
Refinement stepCycle: final / Resolution: 2.299→34.693 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4762 0 413 42 5217
Biso mean--114.61 78.4 -
Num. residues----596
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.299-2.35640.3449260.261572621
2.3564-2.42010.3281550.2692101130
2.4201-2.49130.2808640.2594146843
2.4913-2.57160.2981880.2734181354
2.5716-2.66350.26121160.2469216164
2.6635-2.77010.2811350.2283259377
2.7701-2.89610.28271700.2197303490
2.8961-3.04870.24181580.2183335399
3.0487-3.23960.22161620.21413417100
3.2396-3.48950.24931960.2023362100
3.4895-3.84030.22561880.18233341100
3.8403-4.39510.22211560.18433414100
4.3951-5.53370.21831750.19213403100
5.5337-34.6930.23772070.23913404100
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)
10.2204-0.1545-1.40373.85842.03494.24270.0478-0.36410.37110.20640.3573-0.6049-0.19870.6165-0.15240.2073-0.0152-0.07810.4433-0.10610.589337.4729-4.5263230.1843
22.8897-0.213-0.44795.07210.66182.58090.0180.2715-0.0976-0.73340.1254-0.11540.12550.0784-0.07480.45610.03540.00130.3616-0.00860.287533.1131-26.6732205.4664
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 26:375)A26 - 375
2X-RAY DIFFRACTION2(chain B and resid 45:378)B45 - 378

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