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- PDB-5wiu: Structure of the human D4 Dopamine receptor in complex with Nemon... -

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Basic information

Entry
Database: PDB / ID: 5wiu
TitleStructure of the human D4 Dopamine receptor in complex with Nemonapride
ComponentsD(4) dopamine receptor, soluble cytochrome b562 chimera
KeywordsSIGNALING PROTEIN/ANTAGONIST / GPCR / dopamine receptor / antagonist / sodium / SIGNALING PROTEIN-ANTAGONIST complex
Function / homology
Function and homology information


positive regulation of dopamine uptake involved in synaptic transmission / positive regulation of sodium:proton antiporter activity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / epinephrine binding / dopamine neurotransmitter receptor activity / Dopamine receptors / adenylate cyclase-inhibiting dopamine receptor signaling pathway / dopamine binding / negative regulation of voltage-gated calcium channel activity ...positive regulation of dopamine uptake involved in synaptic transmission / positive regulation of sodium:proton antiporter activity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / epinephrine binding / dopamine neurotransmitter receptor activity / Dopamine receptors / adenylate cyclase-inhibiting dopamine receptor signaling pathway / dopamine binding / negative regulation of voltage-gated calcium channel activity / behavioral response to ethanol / regulation of dopamine metabolic process / fear response / G protein-coupled serotonin receptor activity / inhibitory postsynaptic potential / positive regulation of kinase activity / regulation of postsynaptic neurotransmitter receptor internalization / norepinephrine binding / neurotransmitter receptor activity / G protein-coupled dopamine receptor signaling pathway / arachidonic acid secretion / dopamine metabolic process / social behavior / behavioral response to cocaine / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / potassium channel regulator activity / negative regulation of protein secretion / behavioral fear response / response to amphetamine / adult locomotory behavior / electron transport chain / positive regulation of MAP kinase activity / regulation of circadian rhythm / SH3 domain binding / intracellular calcium ion homeostasis / rhythmic process / G alpha (i) signalling events / postsynapse / chemical synaptic transmission / periplasmic space / electron transfer activity / iron ion binding / centrosome / glutamatergic synapse / dendrite / heme binding / identical protein binding / membrane / metal ion binding / plasma membrane
Similarity search - Function
Dopamine D4 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
Nemonapride / OLEIC ACID / DI(HYDROXYETHYL)ETHER / PHOSPHATE ION / Soluble cytochrome b562 / D(4) dopamine receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.962 Å
AuthorsWacker, D. / Wang, S. / Levit, A. / Che, T. / Betz, R.M. / McCorvy, J.D. / Venkatakrishnan, A.J. / Huang, X.-P. / Dror, R.O. / Shoichet, B.K. / Roth, B.L.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)R01MH112205 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)HHSN-271-2013-00017-C United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)U19MH082441 United States
University of North CarolinaUNC Michael Hooker Chair for Protein Therapeutics and Translational Proteomics United States
CitationJournal: Science / Year: 2017
Title: D4 dopamine receptor high-resolution structures enable the discovery of selective agonists.
Authors: Wang, S. / Wacker, D. / Levit, A. / Che, T. / Betz, R.M. / McCorvy, J.D. / Venkatakrishnan, A.J. / Huang, X.P. / Dror, R.O. / Shoichet, B.K. / Roth, B.L.
History
DepositionJul 20, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 17, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 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

Downloads & links

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Assembly

Deposited unit
A: D(4) dopamine receptor, soluble cytochrome b562 chimera
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,56924
Polymers45,3071
Non-polymers4,26223
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7270 Å2
ΔGint10 kcal/mol
Surface area19540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.688, 164.047, 84.129
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-1203-

PO4

21A-1204-

PO4

31A-1393-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein D(4) dopamine receptor, soluble cytochrome b562 chimera / D(2C) dopamine receptor / Dopamine D4 receptor / Cytochrome b-562


Mass: 45306.602 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: DRD4, cybC / Plasmid: pFastBac1-HM / Production host: Insecta (insects) / References: UniProt: P21917, UniProt: P0ABE7

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Non-polymers , 6 types, 121 molecules

#2: Chemical ChemComp-AQD / Nemonapride / N-[(2R,3R)-1-benzyl-2-methylpyrrolidin-3-yl]-5-chloro-2-methoxy-4-(methylamino)benzamide


Mass: 387.903 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H26ClN3O2 / Comment: antipsychotic*YM
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#4: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C18H34O2
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / Source method: isolated from a natural source / Formula: H2O

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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: 2.57 Å3/Da / Density % sol: 52.2 %
Crystal growTemperature: 298 K / Method: lipidic cubic phase
Details: 100 mM Tris-HCl, pH 5.8-6.2, 160-200 mM ammonium phosphate dibasic, 34% PEG400

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2015
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.95→30 Å / Num. obs: 33049 / % possible obs: 97.9 % / Redundancy: 3.9 % / Biso Wilson estimate: 41.61 Å2 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.073 / Rrim(I) all: 0.149 / Χ2: 1.586 / Net I/σ(I): 11.9 / Num. measured all: 128148
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.95-2.013.80.8470.6520.4830.9810.78997.8
2.01-2.073.90.5570.7640.3110.6420.94198.6
2.07-2.153.90.4070.8810.2250.4681.08798.4
2.15-2.233.90.3220.9050.180.3711.29198.3
2.23-2.333.90.2550.9340.1430.2941.39798.5
2.33-2.463.80.2080.9520.1180.241.60298.6
2.46-2.613.90.1670.9640.0930.1921.7498.3
2.61-2.814.10.1370.9740.0740.1571.75398.6
2.81-3.0940.1150.980.0630.1322.19598
3.09-3.543.90.0970.9850.0540.1122.04897.4
3.54-4.463.90.10.9780.0560.1162.09397.7
4.46-303.60.1390.9350.0820.1632.05894.6

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Processing

Software
NameVersionClassification
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 3PBL & 1M6T

3pbl

1m6t


Resolution: 1.962→25.59 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2362 1599 4.84 %
Rwork0.2049 --
obs0.2065 33027 97.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 112.35 Å2 / Biso mean: 50.4734 Å2 / Biso min: 26.89 Å2
Refinement stepCycle: final / Resolution: 1.962→25.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2736 0 275 98 3109
Biso mean--58.49 51.44 -
Num. residues----373
LS refinement shellResolution: 1.9616→2.0249 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.339 124 -
Rwork0.2895 2642 -
obs--91.1 %
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)
11.6322-0.73910.22262.076-0.14781.83750.04490.0656-0.0783-0.04910.10640.21730.0899-0.1163-0.13990.2301-0.0315-0.02960.26520.01890.2409-17.88571.1583-13.2564
26.6866.40290.89498.25080.96732.06940.0204-0.25450.82770.5227-0.10740.4157-0.1720.17970.20540.5216-0.0160.03490.3652-0.07380.5651-15.9784-40.6783-10.9566
32.4309-0.58320.31953.09590.01971.94280.0860.1057-0.2739-0.2537-0.03660.20630.2583-0.0717-0.03260.2321-0.0097-0.00110.2682-0.01410.2217-11.77750.5159-21.6447
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 34 through 227 )A34 - 227
2X-RAY DIFFRACTION2chain 'A' and (resid 1001 through 1106 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 383 through 462 )A383 - 462

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