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- PDB-6tq7: Crystal structure of the Orexin-1 receptor in complex with SB-334867 -

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Basic information

Entry
Database: PDB / ID: 6tq7
TitleCrystal structure of the Orexin-1 receptor in complex with SB-334867
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-NVK / Chem-PGW / Orexin/Hypocretin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6636 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: 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 / 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)89,90822
Polymers83,4522
Non-polymers6,45620
Water34219
1
A: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,36912
Polymers41,7261
Non-polymers3,64311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Orexin receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,53910
Polymers41,7261
Non-polymers2,8149
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.766, 148.243, 71.668
Angle α, β, γ (deg.)90.000, 112.170, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 45 through 187 or resid 199 through 377 or resid 401 through 501))
21(chain B and (resid 45 through 377 or resid 401 through 501))

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
11TYRTYRSERSER(chain A and (resid 45 through 187 or resid 199 through 377 or resid 401 through 501))AA45 - 18721 - 163
12PHEPHELEULEU(chain A and (resid 45 through 187 or resid 199 through 377 or resid 401 through 501))AA199 - 377175 - 353
13NVKNVKHOHHOH(chain A and (resid 45 through 187 or resid 199 through 377 or resid 401 through 501))AC - W401 - 501
21TYRTYRLEULEU(chain B and (resid 45 through 377 or resid 401 through 501))BB45 - 37721 - 353
22NVKNVKHOHHOH(chain B and (resid 45 through 377 or resid 401 through 501))BN - X401 - 501

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Components

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Protein / Sugars , 2 types, 13 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: SB-334867 bound in the orthosteric site / Source: (gene. exp.) Homo sapiens (human) / Gene: HCRTR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43613
#4: 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.: 11
Source method: isolated from a genetically manipulated source
Formula: C14H28O5S / Comment: detergent*YM

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Non-polymers , 4 types, 28 molecules

#2: Chemical
ChemComp-NVK / 1-(2-methyl-1,3-benzoxazol-6-yl)-3-(1,5-naphthyridin-4-yl)urea


Mass: 319.317 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H13N5O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist, medication*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / 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: 3.86 Å3/Da / Density % sol: 68.09 %
Crystal growTemperature: 284 K / Method: vapor diffusion, sitting drop / pH: 5.2
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 S 6M / Detector: PIXEL / Date: Oct 31, 2012
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.6636→33.9233 Å / Num. obs: 19273 / % possible obs: 58.39 % / Redundancy: 5.3 % / CC1/2: 0.997 / Net I/σ(I): 10.6
Reflection shellResolution: 2.6636→2.804 Å / Num. unique obs: 184 / CC1/2: 0.336

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6TO7

6to7


Resolution: 2.6636→33.921 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 37.91
RfactorNum. reflection% reflection
Rfree0.2551 963 5 %
Rwork0.2203 --
obs0.2221 19273 58.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 183.75 Å2 / Biso mean: 71.0365 Å2 / Biso min: 13.88 Å2
Refinement stepCycle: final / Resolution: 2.6636→33.921 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4878 0 440 19 5337
Biso mean--97.48 46.4 -
Num. residues----612
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2730X-RAY DIFFRACTION10.347TORSIONAL
12B2730X-RAY DIFFRACTION10.347TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.664-2.8040.318880.31951764
2.804-2.97960.4162490.304777718
2.9796-3.20950.3375790.288165737
3.2095-3.53220.34161220.2591270560
3.5322-4.04260.26711960.2099403290
4.0426-5.09040.22672650.18994440100
5.0904-33.9210.24562440.2334523100
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)
12.33780.6301-0.63754.2872-1.17812.34290.0741-0.34130.02780.61450.09040.10230.16660.0756-0.03770.2559-0.0071-0.02030.2041-0.03360.139534.3464-25.9828-7.8831
20.97890.2542-0.94944.0362-2.03593.70060.08890.33420.219-0.27120.43670.7210.0738-0.7253-0.1448-0.0128-0.0569-0.18520.41750.15430.539429.1766-4.0026-33.1519
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 45:377)A45 - 377
2X-RAY DIFFRACTION2(chain B and resid 25:378)B25 - 378

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