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- PDB-6tq6: Crystal structure of the Orexin-1 receptor in complex with Compound 14 -

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Basic information

Entry
Database: PDB / ID: 6tq6
TitleCrystal structure of the Orexin-1 receptor in complex with Compound 14
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 / G alpha (q) signalling events ...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 / G alpha (q) signalling events / chemical synaptic transmission / 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-NVH / Chem-PGW / Orexin/Hypocretin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.546 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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)89,80422
Polymers83,4522
Non-polymers6,35220
Water46826
1
A: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,59310
Polymers41,7261
Non-polymers2,8689
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,21012
Polymers41,7261
Non-polymers3,48411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.834, 147.072, 72.260
Angle α, β, γ (deg.)90.000, 111.560, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 45 through 375 or resid 401))
21(chain B and (resid 45 through 187 or resid 199 through 244 or resid 289 through 375 or resid 401))

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11TYRTYRTRPTRP(chain A and (resid 45 through 375 or resid 401))AA45 - 37521 - 351
12NVHNVHNVHNVH(chain A and (resid 45 through 375 or resid 401))AC401
21TYRTYRSERSER(chain B and (resid 45 through 187 or resid 199 through 244 or resid 289 through 375 or resid 401))BB45 - 18721 - 163
22PHEPHEGLYGLY(chain B and (resid 45 through 187 or resid 199 through 244 or resid 289 through 375 or resid 401))BB199 - 244175 - 220
23GLNGLNTRPTRP(chain B and (resid 45 through 187 or resid 199 through 244 or resid 289 through 375 or resid 401))BB289 - 375265 - 351
24NVHNVHNVHNVH(chain B and (resid 45 through 187 or resid 199 through 244 or resid 289 through 375 or resid 401))BL401

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Components

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Protein / Sugars , 2 types, 12 molecules AB

#1: Protein Orexin receptor type 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 14 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


Type: D-saccharide / Mass: 308.434 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Formula: C14H28O5S / Comment: detergent*YM

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Non-polymers , 5 types, 36 molecules

#2: Chemical ChemComp-NVH / 2-(5-methylsulfonylpyridin-3-yl)-1,1-bis(oxidanylidene)-4-[[2,4,6-tris(fluoranyl)phenyl]methyl]pyrido[2,3-e][1,2,4]thiadiazin-3-one


Mass: 498.456 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H13F3N4O5S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 749.007 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C40H77O10P / Comment: phospholipid*YM
#6: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 3.88 Å3/Da / Density % sol: 68.28 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 5
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: 0.96863 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 14, 2013
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96863 Å / Relative weight: 1
ReflectionResolution: 2.54→34.064 Å / Num. obs: 29926 / % possible obs: 78.7 % / Redundancy: 8.4 % / CC1/2: 0.998 / Net I/σ(I): 11.2
Reflection shellResolution: 2.54→2.62 Å / Num. unique obs: 443 / CC1/2: 0.368

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6TO7

6to7


Resolution: 2.546→34.064 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 34.95
RfactorNum. reflection% reflection
Rfree0.2626 1482 4.95 %
Rwork0.2229 --
obs0.2249 29926 78.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 193.11 Å2 / Biso mean: 80.7725 Å2 / Biso min: 25.08 Å2
Refinement stepCycle: final / Resolution: 2.546→34.064 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4744 0 412 26 5182
Biso mean--104.93 72.72 -
Num. residues----594
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2544X-RAY DIFFRACTION7.349TORSIONAL
12B2544X-RAY DIFFRACTION7.349TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.546-2.62770.5807190.701342413
2.6277-2.72160.3302950.2936142844
2.7216-2.83050.3433960.2765191558
2.8305-2.95930.27181100.2607237573
2.9593-3.11520.26931630.239270782
3.1152-3.31020.2471360.2431311895
3.3102-3.56560.25581760.21613285100
3.5656-3.92390.21171450.18893298100
3.9239-4.49060.26841410.18833315100
4.4906-5.65350.22792130.20043258100
5.6535-34.0640.29281880.24523321100
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)
18.6546-1.8887-0.88432.3974.39019.12480.5007-0.9964-0.60470.4921-0.31740.87430.1288-0.5831-0.25811.0089-0.03930.05130.58110.08260.8856-47.527464.8489124.992
20.66820.4535-0.36713.31781.6242.97780.3638-0.19440.3046-0.30360.6446-1.8145-0.66330.8597-0.31510.1774-0.03630.04220.5792-0.28781.1226-22.249950.063598.624
30.1297-0.75160.16275.126-0.3011.19910.3590.2166-0.3388-0.74490.4275-1.90050.47870.9317-0.66030.50490.06690.12380.7786-0.24281.3014-14.578334.937886.5176
41.28450.2118-0.71782.86544.28887.3460.4483-0.2660.5033-1.2801-0.37821.1382-0.7976-0.7541-0.05580.53620.1169-0.00550.5670.05050.74-41.82653.646687.7583
52.52860.5009-0.90224.59772.23473.7074-0.1028-0.40370.11080.83410.4009-1.09550.42830.7979-0.0680.33350.1397-0.14530.4808-0.03640.5973-26.580333.9839100.2424
60.36540.5398-0.056.43921.7815.68010.4951-0.1360.00080.5353-0.0020.3101-0.14950.048-0.11150.36070.0431-0.0340.3754-0.04680.575-34.161248.0877105.5165
71.93882.1946-1.35352.5051-1.3393.6679-0.2265-0.0609-0.1260.256-1.3611-0.5359-0.671.44220.16550.61280.0527-0.57741.7747-0.46171.8738-4.215348.3761108.2752
83.2142-0.7255-1.8584.26811.83965.25970.08160.52710.0559-0.85370.0513-0.54510.3459-0.1049-0.14181.33180.15430.19250.4954-0.09420.1373-29.447913.450365.6115
92.5279-0.46990.24294.3316-0.42753.99240.11120.4979-0.0931-1.38930.3701-0.76150.3980.22450.08240.8010.14810.41070.363-0.04720.5483-26.309617.347973.2102
103.2295-1.37750.14094.04790.89182.78640.05340.15610.3717-0.99190.5857-1.4554-0.12990.2155-0.21250.48130.07120.39360.3002-0.07730.5973-22.877829.930279.1182
110.7244-0.38440.13694.1321.80790.8815-0.2874-0.1945-0.4831.47240.19120.58680.62320.00960.13020.76250.07370.22580.39820.12950.4789-35.852812.515593.294
122.35430.8497-0.90783.6443-0.93242.35020.38670.90231.1558-2.34660.2925-0.3065-1.134-0.1372-0.10351.57010.03030.30820.53480.30870.7042-33.511445.459768.771
135.45032.1959-2.4995.3712-1.82294.1410.21110.56510.3152-1.3568-0.1726-0.2467-0.63990.3722-0.13550.96270.03370.19180.36340.09630.2036-34.36132.742369.67
143.00853.6225-0.2414.4886-1.10566.4866-0.0317-0.2593-0.28780.76460.10772.06961.4922-2.45410.67050.9013-0.18660.16811.1536-0.04611.095-51.598515.999990.2459
154.6568-2.27860.44594.24792.32854.96060.226-0.0841-0.0528-1.0575-0.16740.25290.16790.5099-0.00920.7161-0.0305-0.06250.31620.00710.3572-38.789617.403971.9515
161.1424-0.51921.88851.00420.55735.72820.49450.6453-0.1456-1.3388-0.1646-0.44041.85090.58270.69343.01780.13450.68870.96350.05260.9489-22.610120.730253.6489
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 28 through 39 )A28 - 39
2X-RAY DIFFRACTION2chain 'A' and (resid 40 through 148 )A40 - 148
3X-RAY DIFFRACTION3chain 'A' and (resid 149 through 175 )A149 - 175
4X-RAY DIFFRACTION4chain 'A' and (resid 176 through 208 )A176 - 208
5X-RAY DIFFRACTION5chain 'A' and (resid 209 through 322 )A209 - 322
6X-RAY DIFFRACTION6chain 'A' and (resid 323 through 361 )A323 - 361
7X-RAY DIFFRACTION7chain 'A' and (resid 362 through 375 )A362 - 375
8X-RAY DIFFRACTION8chain 'B' and (resid 45 through 73 )B45 - 73
9X-RAY DIFFRACTION9chain 'B' and (resid 74 through 114 )B74 - 114
10X-RAY DIFFRACTION10chain 'B' and (resid 115 through 175 )B115 - 175
11X-RAY DIFFRACTION11chain 'B' and (resid 176 through 224 )B176 - 224
12X-RAY DIFFRACTION12chain 'B' and (resid 225 through 251 )B225 - 251
13X-RAY DIFFRACTION13chain 'B' and (resid 252 through 322 )B252 - 322
14X-RAY DIFFRACTION14chain 'B' and (resid 323 through 332 )B323 - 332
15X-RAY DIFFRACTION15chain 'B' and (resid 333 through 361 )B333 - 361
16X-RAY DIFFRACTION16chain 'B' and (resid 362 through 377 )B362 - 377

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