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- PDB-6v9s: Structure-based development of subtype-selective orexin 1 recepto... -

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Basic information

Entry
Database: PDB / ID: 6v9s
TitleStructure-based development of subtype-selective orexin 1 receptor antagonists
ComponentsOrexin receptor type 1,GlgA glycogen synthase chimera
KeywordsSIGNALING PROTEIN / GPCR / orexin receptor / selective ligand
Function / homology
Function and homology information


orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / glycogen (starch) synthase activity / feeding behavior / glycogen biosynthetic process / peptide hormone binding / neuropeptide signaling pathway / cellular response to hormone stimulus / regulation of cytosolic calcium ion concentration / G protein-coupled receptor activity ...orexin receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / glycogen (starch) synthase activity / feeding behavior / glycogen biosynthetic process / 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 / cytosol
Similarity search - Function
Orexin/Hypocretin receptor type 1 / 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 ...Orexin/Hypocretin receptor type 1 / 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
CHOLESTEROL / Chem-JHC / OLEIC ACID / Orexin/Hypocretin receptor type 1 / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsHellmann, J. / Drabek, M. / Yin, J. / Huebner, H. / Kraus, F. / Proell, T. / Weikert, D. / Kolb, P. / Rosenbaum, D.M. / Gmeiner, P.
Funding support United States, 1items
OrganizationGrant numberCountry
Welch FoundationI-1770 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2020
Title: Structure-based development of a subtype-selective orexin 1 receptor antagonist.
Authors: Hellmann, J. / Drabek, M. / Yin, J. / Gunera, J. / Proll, T. / Kraus, F. / Langmead, C.J. / Hubner, H. / Weikert, D. / Kolb, P. / Rosenbaum, D.M. / Gmeiner, P.
History
DepositionDec 16, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Aug 12, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 11, 2023Group: 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 1,GlgA glycogen synthase chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,9054
Polymers62,7431
Non-polymers1,1623
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.661, 66.341, 182.461
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Orexin receptor type 1,GlgA glycogen synthase chimera / Ox1R / Hypocretin receptor type 1 / Glycogen synthase


Mass: 62743.133 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: HCRTR1, PAB2292 / Strain: GE5 / Orsay / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O43613, UniProt: Q9V2J8
#2: Chemical ChemComp-JHC / [(2S)-2-[(2S)-butan-2-yl]-4-(5-chloro-1,3-benzoxazol-2-yl)-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone


Mass: 493.000 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H34O2
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: 3.12 Å3/Da / Density % sol: 60.56 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100mM Sodium Citrate pH 5.3, 31% PEG 400, 200 mM Ammonium Formate
PH range: 5.5-6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 9356 / % possible obs: 89.2 % / Redundancy: 2.7 % / Rmerge(I) obs: 0.197 / Rpim(I) all: 0.129 / Rrim(I) all: 0.237 / Χ2: 0.818 / Net I/σ(I): 4 / Num. measured all: 24855
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.5-3.562.61.2354900.2860.8271.4980.93694.4
3.56-3.632.50.8824420.3510.6151.0850.96590
3.63-3.692.70.7524630.540.5070.9150.87888.7
3.69-3.772.70.6564700.640.430.7910.90193.8
3.77-3.852.80.5724800.7260.3610.6820.99192
3.85-3.942.70.5274560.7160.3450.6350.94590.5
3.94-4.042.70.4615010.7910.3030.5560.94593.3
4.04-4.152.70.3614380.8760.2390.4370.76887.8
4.15-4.272.60.3594840.8610.2310.4310.9694.2
4.27-4.412.70.2774680.9070.1770.3310.91789
4.41-4.572.50.1854600.9610.1240.2250.84790.6
4.57-4.752.50.1584590.9660.1070.1920.77787.9
4.75-4.972.60.134740.9760.0860.1570.8591.3
4.97-5.232.70.1334510.980.0870.1610.74686.7
5.23-5.552.50.1384740.960.0940.1690.6388.6
5.55-5.982.80.1514660.9560.0950.180.72789.8
5.98-6.582.90.1274710.9530.0770.1490.62588
6.58-7.532.60.094730.9770.0570.1070.65188.4
7.53-9.482.50.0434660.9910.0280.0510.63284
9.48-502.60.0344700.9950.0220.0410.63677.8

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
SCALEPACKdata scaling
PDB_EXTRACT3.25data extraction
SCALEPACKdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZJ8, 4ZJC

4zj8

4zjc


Resolution: 3.5→44.88 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 25.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2732 612 7.51 %
Rwork0.2388 7534 -
obs0.2415 8146 77.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 176.88 Å2 / Biso mean: 63.9955 Å2 / Biso min: 26.69 Å2
Refinement stepCycle: final / Resolution: 3.5→44.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4031 0 83 0 4114
Biso mean--63.63 --
Num. residues----503
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.5-3.850.2969970.29291226132352
3.85-4.410.29011640.25572036220085
4.41-5.550.26921860.22392097228388
5.55-44.880.25161650.21732175234086
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)
17.4203-1.6588-2.55255.9548-2.99953.54560.0947-0.93840.80710.9116-0.3730.219-1.04370.26090.18980.89920.0386-0.06030.3798-0.10140.69161.81131.7173-77.9491
24.6058-1.1872-0.41143.28274.6776.59040.201-0.127-0.20240.4364-0.1259-0.03470.581-0.2301-0.10760.5509-0.0105-0.03230.2648-0.03590.3897-4.5329-2.9995-40.1305
34.4257-0.8244-2.62165.280.02253.51360.1666-1.00710.11540.8347-0.95350.69520.096-0.28840.86580.5242-0.21790.19360.9857-0.33180.8346-17.4052-6.301-39.5567
41.6734-0.01290.1050.4192-0.1970.10660.73251.17930.2009-0.2231-0.53950.62940.0981-2.6251-0.17680.5359-0.0137-0.04731.1996-0.13620.6559-8.6939-7.4381-73.3769
53.0581-1.0747-0.78992.7199-0.49790.53660.15130.30350.1601-0.7241-0.68180.8467-0.2266-1.38250.62290.41740.0723-0.00110.6111-0.01740.5371-14.76459.6033-44.4366
64.6042-0.42830.36464.28665.49287.4508-0.7222-0.2330.58290.369-0.09930.7019-0.59120.84960.69250.4711-0.01340.02920.30770.0410.4754-3.112610.3802-28.2109
75.1076-1.06130.02246.5026-0.37964.62870.18440.33690.1581-1.257-0.0578-0.58790.3205-0.6945-0.16270.4406-0.06360.09880.4445-0.23460.5748-0.5225.5251-47.9965
86.9557-2.2595-4.20318.40917.3142.0328-0.5417-1.4390.13521.03980.27480.58330.51161.54170.32620.5163-0.0653-0.00720.6550.06610.50565.311321.35466.1747
96.07420.00223.09613.3278-0.60614.6488-1.1486-0.51310.430.20930.08250.0261-0.9634-0.73760.94750.49620.17120.11840.6919-0.2940.6512-7.473131.99873.7172
108.631-0.66123.45083.572-2.47658.34090.405-1.4971.17921.05951.24850.2185-1.5932-1.7933-1.62850.65470.44370.02060.7814-0.00480.8584-17.462734.58529.4333
119.7625-0.055-0.53365.9025-4.21112.0581-0.8479-0.93980.67490.33131.1885-0.99380.8048-1.4032-0.45520.90860.0686-0.11910.8395-0.26430.6369-8.697331.966311.1912
122.00472.2594-5.63414.5647-3.38347.38380.2031-1.59611.7907-0.20350.24131.2851-2.57450.6616-0.5351.04530.134-0.01940.9366-0.2450.9973-9.553543.58965.4154
131.86280.8526-2.9728.6021-2.73238.41040.4717-0.78111.77481.28770.6566-0.7767-1.45630.8964-1.09770.73640.1171-0.19790.7898-0.25930.6537-1.268736.84396.682
146.7683-0.5279-0.24322.7872.68934.55480.31830.6760.2857-0.76270.3333-0.2737-1.31210.5607-0.56170.4108-0.13070.09010.58150.02950.4439-3.676224.3346-1.3586
154.4607-4.19662.65685.7816-3.37543.54850.0053-0.9023-0.2996-0.53050.40161.01310.8197-1.7173-0.21460.34370.2361-0.02030.77860.09130.6647-14.96919.4573-1.8546
161.1031-0.93410.63963.2399-1.08092.01280.0435-0.9197-0.19850.43510.440.8296-0.1871-0.9525-0.53870.5340.28310.08461.57120.04290.5682-17.255822.821110.8547
176.1715-2.4731-2.37014.94347.50672.0328-0.2752-0.4152-1.13211.1458-0.8322-0.26041.75890.82481.07940.6763-0.0094-0.15790.53220.30320.6993-5.253211.37822.3513
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 26 through 45 )A26 - 45
2X-RAY DIFFRACTION2chain 'A' and (resid 46 through 157 )A46 - 157
3X-RAY DIFFRACTION3chain 'A' and (resid 158 through 181 )A158 - 181
4X-RAY DIFFRACTION4chain 'A' and (resid 182 through 200 )A182 - 200
5X-RAY DIFFRACTION5chain 'A' and (resid 201 through 246 )A201 - 246
6X-RAY DIFFRACTION6chain 'A' and (resid 288 through 310 )A288 - 310
7X-RAY DIFFRACTION7chain 'A' and (resid 311 through 373 )A311 - 373
8X-RAY DIFFRACTION8chain 'A' and (resid 1001 through 1027 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 1028 through 1047 )A0
10X-RAY DIFFRACTION10chain 'A' and (resid 1048 through 1062 )A0
11X-RAY DIFFRACTION11chain 'A' and (resid 1063 through 1075 )A0
12X-RAY DIFFRACTION12chain 'A' and (resid 1076 through 1089 )A0
13X-RAY DIFFRACTION13chain 'A' and (resid 1090 through 1101 )A0
14X-RAY DIFFRACTION14chain 'A' and (resid 1102 through 1134 )A0
15X-RAY DIFFRACTION15chain 'A' and (resid 1135 through 1162 )A0
16X-RAY DIFFRACTION16chain 'A' and (resid 1163 through 1178 )A0
17X-RAY DIFFRACTION17chain 'A' and (resid 1179 through 1196 )A0

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