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- PDB-6tpg: Crystal structure of the Orexin-2 receptor in complex with EMPA a... -

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Basic information

Entry
Database: PDB / ID: 6tpg
TitleCrystal structure of the Orexin-2 receptor in complex with EMPA at 2.74 A resolution
ComponentsOrexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-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 / locomotion / feeding behavior / peptide hormone binding / neuropeptide signaling pathway ...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 / locomotion / feeding behavior / 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 / chemical synaptic transmission / G alpha (q) signalling events / nucleotide binding / synapse / plasma membrane
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
Chem-7MA / OLEIC ACID / Orexin receptor type 2 / Orexin receptor type 2 / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi GE5 (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.741 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

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Assembly

Deposited unit
A: Orexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,4514
Polymers64,5201
Non-polymers9313
Water1,00956
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area860 Å2
ΔGint4 kcal/mol
Surface area24830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.097, 172.914, 77.810
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Orexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-2 / Ox2R / Hypocretin receptor type 2 / Glycogen synthase / cDNA / FLJ95033 / Homo sapiens hypocretin ...Ox2R / Hypocretin receptor type 2 / Glycogen synthase / cDNA / FLJ95033 / Homo sapiens hypocretin (orexin) receptor 2 (HCRTR2) / mRNA


Mass: 64520.121 Da / Num. of mol.: 1
Mutation: E54A Y91L D100A V142A R170L L206A Y219A M233A A242L L310V L318A T347A N14D N22D N202D C381W C382W C383W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Pyrococcus abyssi GE5 (archaea)
Gene: HCRTR2, PAB2292 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43614, UniProt: Q9V2J8, UniProt: Q548Y0
#2: Chemical ChemComp-7MA / N-ethyl-2-[(6-methoxypyridin-3-yl)-(2-methylphenyl)sulfonyl-amino]-N-(pyridin-3-ylmethyl)ethanamide / EMPA (drug)


Mass: 454.542 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N4O4S / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H34O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 56 / Source method: isolated from a natural source / Formula: H2O
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: 2.37 Å3/Da / Density % sol: 48.2 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100 mM trisodium citrate buffer 150-300 mM sodium chloride 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: 0.96861 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 2.74→45.55 Å / Num. obs: 11345 / % possible obs: 89.1 % / Redundancy: 8 % / CC1/2: 0.977 / Net I/σ(I): 6.7
Reflection shellResolution: 2.74→2.98 Å / Num. unique obs: 475 / CC1/2: 0.346

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQC

5wqc


Resolution: 2.741→45.548 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.71
RfactorNum. reflection% reflection
Rfree0.2752 499 4.4 %
Rwork0.2178 --
obs0.2203 11345 68.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 103.3 Å2 / Biso mean: 41.959 Å2 / Biso min: 0.94 Å2
Refinement stepCycle: final / Resolution: 2.741→45.548 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4048 0 82 56 4186
Biso mean--43.87 23.49 -
Num. residues----504
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.741-3.01640.4037350.296354014
3.0164-3.45270.32441090.257243262
3.4527-4.34960.24991740.2129387698
4.3496-45.54580.2681810.2035399898
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)
11.5133-0.5774-0.16941.26480.5430.8984-0.04960.00510.0389-0.1740.0955-0.0611-0.12460.0211-0.00830.2126-0.0204-0.0087-0.0971-0.00950.536392.6198213.39540.3373
21.4376-0.7281-0.43433.2923-0.04241.42080.0290.2233-0.2476-0.3832-0.18360.3130.0648-0.12260.14930.3541-0.03710.02540.1258-0.1120.5613117.1252170.1043-17.8166
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 37:388)A37 - 388
2X-RAY DIFFRACTION2(chain A and resid 1001:1196)A1001 - 1196

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