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- PDB-6tod: Crystal structure of the Orexin-1 receptor in complex with EMPA -

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Basic information

Entry
Database: PDB / ID: 6tod
TitleCrystal structure of the Orexin-1 receptor in complex with EMPA
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
Chem-7MA / CITRIC ACID / Chem-PGW / Orexin/Hypocretin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.11 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 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

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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)94,72764
Polymers76,3262
Non-polymers18,40162
Water3,801211
1
A: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,04631
Polymers38,1631
Non-polymers8,88330
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,68133
Polymers38,1631
Non-polymers9,51832
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.907, 158.891, 182.354
Angle α, β, γ (deg.)90, 95.77, 90
Int Tables number5
Space group name H-MI121

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Components

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Protein / Sugars , 2 types, 49 molecules AB

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


Mass: 38162.879 Da / Num. of mol.: 2
Mutation: E46A I85L V95A A127T R162L N194A L198A Y211A L304V C339A C375W C376W
Source method: isolated from a genetically manipulated source
Details: EMPA bound in orthosteric site / Source: (gene. exp.) Homo sapiens (human) / Gene: HCRTR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43613
#6: 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.: 47
Source method: isolated from a genetically manipulated source
Formula: C14H28O5S / Comment: detergent*YM

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Non-polymers , 7 types, 226 molecules

#2: Chemical ChemComp-7MA / N-ethyl-2-[(6-methoxypyridin-3-yl)-(2-methylphenyl)sulfonyl-amino]-N-(pyridin-3-ylmethyl)ethanamide


Mass: 454.542 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H26N4O4S / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#7: 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
#8: Chemical ChemComp-NA / SODIUM ION


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


Mass: 18.015 Da / Num. of mol.: 211 / 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 / pH: 6.3
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: 0.9686 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 8, 2013
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.11→30.62 Å / Num. obs: 57581 / % possible obs: 61.3 % / Redundancy: 3.3 % / CC1/2: 0.893 / Net I/σ(I): 9.3
Reflection shellResolution: 2.11→2.28 Å / Redundancy: 3.6 % / Num. unique obs: 1152 / CC1/2: 0.01 / % possible all: 5.98

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6TO7

6to7


Resolution: 2.11→30.62 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.919 / SU R Cruickshank DPI: 0.197 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.193 / SU Rfree Blow DPI: 0.163 / SU Rfree Cruickshank DPI: 0.166
RfactorNum. reflection% reflectionSelection details
Rfree0.208 2826 -RANDOM
Rwork0.188 ---
obs0.189 57581 61.3 %-
Displacement parametersBiso mean: 49.1 Å2
Baniso -1Baniso -2Baniso -3
1-0.7715 Å20 Å21.9762 Å2
2---2.9684 Å20 Å2
3---2.1969 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.11→30.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4876 0 862 211 5949
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015963HARMONIC2
X-RAY DIFFRACTIONt_angle_deg17979HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2254SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes821HARMONIC5
X-RAY DIFFRACTIONt_it5963HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_chiral_improper_torsion771SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6676SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion16.97
LS refinement shellResolution: 2.11→2.28 Å
RfactorNum. reflection% reflection
Rfree0.2591 48 -
Rwork0.2331 --
obs0.2341 1152 5.98 %
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)
11.42590.1973-0.50581.9266-0.24581.455-0.0882-0.31480.2134-0.31480.0428-0.11680.2134-0.11680.0455-0.081-0.03950.0072-0.186-0.0121-0.145216.02913.424723.8437
21.7308-0.031-0.09181.2510.08510.60120.0270.0321-0.05930.03210.00770.05-0.05930.05-0.0348-0.1505-0.00050.0201-0.1231-0.0766-0.073926.965330.157740.3921
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|45 - 378}
2X-RAY DIFFRACTION2{B|29 - 383}

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