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- PDB-6tpj: Crystal structure of the Orexin-2 receptor in complex with suvore... -

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Basic information

Entry
Database: PDB / ID: 6tpj
TitleCrystal structure of the Orexin-2 receptor in complex with suvorexant at 2.76 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 / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / neuropeptide receptor 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 / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / neuropeptide receptor activity / locomotion / feeding behavior / peptide hormone binding / neuropeptide signaling pathway / regulation of cytosolic calcium ion concentration / cellular response to hormone stimulus / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / synapse / nucleoplasm / 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
AMMONIUM ION / OLEIC ACID / Chem-SUV / 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: 2.74 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 ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry
Revision 1.4Oct 1, 2025Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_modification_feature ...pdbx_entry_details / pdbx_modification_feature / pdbx_validate_symm_contact / struct_conn
Item: _pdbx_entry_details.has_protein_modification

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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,Hypocretin receptor-2
B: Orexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,02445
Polymers129,0402
Non-polymers10,98443
Water4,071226
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A: Orexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,87318
Polymers64,5201
Non-polymers4,35317
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 2,GlgA glycogen synthase,Hypocretin receptor-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,15127
Polymers64,5201
Non-polymers6,63126
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.325, 76.247, 82.737
Angle α, β, γ (deg.)89.990, 85.250, 89.970
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 47 through 388 or resid 2201...
21(chain B and (resid 47 through 340 or (resid 341...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 47 through 388 or resid 2201...A47 - 388
121(chain A and (resid 47 through 388 or resid 2201...A2201
131(chain A and (resid 47 through 388 or resid 2201...A2701
141(chain A and (resid 47 through 388 or resid 2201...A47 - 3901
151(chain A and (resid 47 through 388 or resid 2201...A47 - 3901
161(chain A and (resid 47 through 388 or resid 2201...A47 - 3901
171(chain A and (resid 47 through 388 or resid 2201...A0
211(chain B and (resid 47 through 340 or (resid 341...B47 - 340
221(chain B and (resid 47 through 340 or (resid 341...B341
231(chain B and (resid 47 through 340 or (resid 341...B45 - 4201
241(chain B and (resid 47 through 340 or (resid 341...B45 - 4201
251(chain B and (resid 47 through 340 or (resid 341...B45 - 4201
261(chain B and (resid 47 through 340 or (resid 341...B45 - 4201
271(chain B and (resid 47 through 340 or (resid 341...B45 - 4201

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Components

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Protein , 1 types, 2 molecules AB

#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: 64520.113 Da / Num. of mol.: 2
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

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Non-polymers , 5 types, 269 molecules

#2: Chemical...
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 34 / Source method: obtained synthetically / Formula: C18H34O2
#3: Chemical ChemComp-SUV / [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone / suvorexant


Mass: 450.921 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NH4 / AMMONIUM ION


Mass: 18.038 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: H4N
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 226 / 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

CrystalDensity Matthews: 2.7 Å3/Da / Density % sol: 54.37 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100 mM N-(2-Acetamido)iminodiacetic acid (ADA) 150-300 mM ammonium nitrate 28-43 % (v/v) polyethylene glycol 400
PH range: 6.0-7.0

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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: Jun 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 2.74→47.695 Å / Num. obs: 23784 / % possible obs: 86.3 % / Redundancy: 1.6 % / CC1/2: 0.984 / Net I/σ(I): 2.5
Reflection shellResolution: 2.76→2.974 Å / Num. unique obs: 1189 / CC1/2: 0.5

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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: 2.74→47.695 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 26.6
RfactorNum. reflection% reflection
Rfree0.2536 1140 4.79 %
Rwork0.2071 --
obs0.2092 23783 67.19 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 132.35 Å2 / Biso mean: 42.1686 Å2 / Biso min: 4.3 Å2
Refinement stepCycle: final / Resolution: 2.74→47.695 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7979 0 439 226 8644
Biso mean--54.32 35.43 -
Num. residues----1000
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4731X-RAY DIFFRACTION8.677TORSIONAL
12B4731X-RAY DIFFRACTION8.677TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.7401-2.86480.2534160.22022847
2.8648-3.01580.3314980.2453129232
3.0158-3.20470.31831220.2455221853
3.2047-3.45210.31331700.238296070
3.4521-3.79930.25411950.2009383592
3.7993-4.34880.22981900.18405696
4.3488-5.47770.21712030.1918403496
5.4777-47.6950.24371460.2247396493
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)
11.6660.3519-0.9632.1844-0.28922.59220.02-0.0917-0.05720.0044-0.05460.03050.0768-0.20590.04240.2866-0.02780.09150.1232-0.00920.062916.858619.291533.8534
22.7556-0.2192-0.35712.291-0.44754.0596-0.07510.2286-0.1848-0.015-0.0073-0.05130.01650.07420.03110.3421-0.00280.06380.1401-0.03630.0767-6.072511.805880.5118
31.1848-0.2607-0.72121.97870.54722.85780.02850.07660.0034-0.0084-0.0585-0.04980.03090.14490.01690.34480.0190.09120.136-0.02960.095714.9907-18.696629.6326
42.6262-0.7139-0.2842.59640.96223.7105-0.049-0.1747-0.08610.02210.02410.0394-0.1052-0.04340.02060.3264-0.0450.05130.1234-0.01090.069437.9635-26.3422-17.2899
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 47:388)A47 - 388
2X-RAY DIFFRACTION2(chain A and resid 1001:1196)A1001 - 1196
3X-RAY DIFFRACTION3(chain B and resid 45:388)B45 - 388
4X-RAY DIFFRACTION4(chain B and resid 1001:1196)B1001 - 1196

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