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- PDB-6tpn: Crystal structure of the Orexin-2 receptor in complex with HTL664... -

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Basic information

Entry
Database: PDB / ID: 6tpn
TitleCrystal structure of the Orexin-2 receptor in complex with HTL6641 at 2.61 A resolution
ComponentsOrexin receptor type 2,GlgA glycogen synthase,Orexin receptor type 2
KeywordsMEMBRANE PROTEIN / 7TM / GPCR
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 / glycogen (starch) synthase activity / feeding behavior / locomotion / glycogen biosynthetic process / peptide hormone binding ...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 / glycogen (starch) synthase activity / feeding behavior / locomotion / glycogen biosynthetic process / 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 / cytosol
Similarity search - Function
Orexin receptor 2 / Orexin receptor type 2 / Orexin receptor family / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycosyl transferases group 1 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. ...Orexin receptor 2 / Orexin receptor type 2 / Orexin receptor family / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycosyl transferases group 1 / 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
NITRATE ION / Chem-NU8 / OLEIC ACID / Orexin receptor type 2 / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.608 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 13, 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 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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 2,GlgA glycogen synthase,Orexin receptor type 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,64310
Polymers64,5201
Non-polymers2,1239
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint24 kcal/mol
Surface area25830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.945, 173.950, 78.327
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Orexin receptor type 2,GlgA glycogen synthase,Orexin receptor type 2 / Ox2R / Hypocretin receptor type 2 / Glycogen synthase / Ox2R / Hypocretin receptor type 2


Mass: 64520.121 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Pyrococcus abyssi (strain GE5 / Orsay) (archaea)
Gene: HCRTR2, PAB2292 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43614, UniProt: Q9V2J8

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Non-polymers , 5 types, 55 molecules

#2: Chemical ChemComp-NU8 / 2-(5,6-dimethoxypyridin-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: 480.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H15F3N4O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: HTL-6641*YM
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H34O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.4 Å3/Da / Density % sol: 48.76 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100 mM trisodium citrate buffer 150-300 mM lithium nitrate or 150-300 mM potassium nitrate 28-43 % (v/v) polyethylene glycol 400
PH range: 5.0-6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96863 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96863 Å / Relative weight: 1
ReflectionResolution: 2.608→43.488 Å / Num. obs: 11699 / % possible obs: 91.6 % / Redundancy: 8.3 % / Biso Wilson estimate: 40.91 Å2 / CC1/2: 0.996 / Net I/σ(I): 5.9
Reflection shellResolution: 2.608→2.794 Å / Num. unique obs: 4223 / CC1/2: 0.426

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.13_2998refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQC
Resolution: 2.608→41.475 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.99
RfactorNum. reflection% reflection
Rfree0.251 607 5.19 %
Rwork0.2139 --
obs0.2158 11692 60.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 186.58 Å2 / Biso mean: 56.3158 Å2 / Biso min: 19.31 Å2
Refinement stepCycle: final / Resolution: 2.608→41.475 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4100 0 1909 46 6055
Biso mean--53.96 40.94 -
Num. residues----288
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.608-2.87010.2711320.301548111
2.8701-3.28530.2656940.2723194043
3.2853-4.13850.2642470.2216405189
4.1385-41.4750.23652340.1943461397
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
17.69761.45540.91662.96010.34761.3746-0.5615-1.29470.39010.989-0.11020.3310.2392-0.1995-0.50730.58240.1965-0.06350.4334-0.06521.143975.2828241.19510.4361
21.1701-2.5577-1.96056.81435.01974.4134-0.1310.12980.1246-1.43010.17490.4159-0.3117-0.2078-0.09510.90740.00910.0720.53980.03181.043278.3258239.8581-4.6765
33.4334-1.7036-0.02342.52651.19561.4764-0.0751-0.1101-0.2962-0.21380.0010.2090.0633-0.13170.07610.22530.0152-0.03080.02610.02430.640484.5267212.2762.8264
43.1856-3.3306-1.70565.19542.11181.2521-0.1754-0.3416-0.1355-0.13210.3241-0.2605-0.0117-0.0016-0.03770.24970.05210.01180.13670.04690.626798.0755212.18875.9472
53.1587-1.7994-3.84882.05932.37055.9706-0.5315-0.15270.420.35820.15650.41310.9148-0.12420.18380.32960.0766-0.06270.3559-0.04410.8723109.2627190.94422.9939
63.8053-0.13580.88675.9622-0.23162.3108-0.92940.0426-0.1270.8921.0124-0.62830.21240.5810.05650.56080.17240.01910.3855-0.09620.431100.4302206.46313.2169
72.962-3.0468-0.34063.13330.27911.9945-0.47970.20011.35260.11890.1143-1.0807-0.6497-0.5601-0.2650.49240.0679-0.22360.272-0.0261.161591.7034236.60488.8399
81.2715-1.8716-0.49534.19492.21242.0033-0.2823-0.26370.7001-0.04560.647-0.0618-0.49270.3211-0.33120.4010.00220.03340.3014-0.12560.9584105.447227.44243.565
91.6268-1.0472-0.14538.20053.62272.37140.32270.5437-0.2364-0.8683-0.2006-0.4452-0.23520.038-0.07540.31930.02310.00790.1858-0.10230.7937106.9564198.7914-10.3045
102.8207-2.8476-0.47844.53311.0520.80180.20720.9186-0.2117-1.0247-0.6071.43380.2395-0.73290.37310.79360.0524-0.02890.5491-0.12580.9435106.9055167.6366-26.7123
113.1023-1.98490.02523.0869-0.70662.5986-0.12070.12680.0125-0.2958-0.1968-0.23250.0373-0.0376-0.16110.474-0.00690.07130.0125-0.12680.7117125.1528171.5965-18.3145
121.8815-1.12880.16576.0884-0.07872.63340.08840.2138-0.5876-0.5089-0.4691-0.71760.11670.1314-0.0620.49910.04680.19420.144-0.07420.848125.1099165.4438-20.3481
135.8171-0.6278-0.42262.42640.76351.1349-0.12211.01230.2663-0.6423-0.4176-0.0114-0.1053-0.1831-0.27240.5393-0.01290.03930.1942-0.02730.7233121.6139172.6298-25.2925
141.0865-0.20140.43042.15260.68880.90810.0320.00560.0515-0.1401-0.0120.5557-0.0811-0.1421-0.17410.3234-0.14420.1550.0774-0.08620.9172113.6602178.6066-11.2609
152.6277-1.1576-0.4654.9760.6731.5102-0.0404-0.1424-0.35980.7052-0.16470.25710.3554-0.11280.03820.48640.00960.19480.04950.01820.8714117.8975166.0244-7.7414
161.7947-3.3478-0.70826.87510.5540.8928-0.00390.2236-0.37450.2562-0.12230.20670.0704-0.09510.0770.2786-0.03520.01050.2212-0.02880.632299.5072195.7909-8.6148
172.7011-0.64710.07083.38031.2351.94460.27880.21660.455-0.6031-0.1137-0.1381-0.620.0983-0.07940.52090.0513-0.00340.24960.02120.713591.4404222.9678-7.5066
182.8264-2.06162.81597.00030.88684.38660.2615-0.3308-1.22250.5872-0.03371.7580.5968-0.77791.00630.5512-0.0618-0.00820.2597-0.0341.415576.4023195.2696-0.3606
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 32 through 43 )A32 - 43
2X-RAY DIFFRACTION2chain 'A' and (resid 44 through 53 )A44 - 53
3X-RAY DIFFRACTION3chain 'A' and (resid 54 through 122 )A54 - 122
4X-RAY DIFFRACTION4chain 'A' and (resid 123 through 156 )A123 - 156
5X-RAY DIFFRACTION5chain 'A' and (resid 157 through 165 )A157 - 165
6X-RAY DIFFRACTION6chain 'A' and (resid 166 through 183 )A166 - 183
7X-RAY DIFFRACTION7chain 'A' and (resid 184 through 212 )A184 - 212
8X-RAY DIFFRACTION8chain 'A' and (resid 213 through 232 )A213 - 232
9X-RAY DIFFRACTION9chain 'A' and (resid 233 through 1003 )A233 - 1003
10X-RAY DIFFRACTION10chain 'A' and (resid 1005 through 1027 )A0
11X-RAY DIFFRACTION11chain 'A' and (resid 1028 through 1060 )A0
12X-RAY DIFFRACTION12chain 'A' and (resid 1061 through 1076 )A0
13X-RAY DIFFRACTION13chain 'A' and (resid 1077 through 1117 )A0
14X-RAY DIFFRACTION14chain 'A' and (resid 1118 through 1149 )A0
15X-RAY DIFFRACTION15chain 'A' and (resid 1150 through 1180 )A0
16X-RAY DIFFRACTION16chain 'A' and (resid 1181 through 328 )A1181 - 328
17X-RAY DIFFRACTION17chain 'A' and (resid 329 through 367 )A329 - 367
18X-RAY DIFFRACTION18chain 'A' and (resid 368 through 388 )A368 - 388

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