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- PDB-8zmf: Crystal structure of an inverse agonist antipsychotic drug deriva... -

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Basic information

Entry
Database: PDB / ID: 8zmf
TitleCrystal structure of an inverse agonist antipsychotic drug derivative-bound 5-HT2C
Components5-hydroxytryptamine receptor 2C,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / class A G protein-coupled receptor / inverse agonist
Function / homology
Function and homology information


regulation of corticotropin-releasing hormone secretion / regulation of appetite / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / regulation of nervous system process / Serotonin receptors / serotonin receptor activity ...regulation of corticotropin-releasing hormone secretion / regulation of appetite / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / regulation of nervous system process / Serotonin receptors / serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / serotonin binding / feeding behavior / cGMP-mediated signaling / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fat cell differentiation / behavioral fear response / release of sequestered calcium ion into cytosol / positive regulation of calcium-mediated signaling / locomotory behavior / electron transport chain / intracellular calcium ion homeostasis / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / electron transfer activity / periplasmic space / iron ion binding / dendrite / heme binding / synapse / identical protein binding / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 2C receptor / 5-hydroxytryptamine 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
: / Soluble cytochrome b562 / 5-hydroxytryptamine receptor 2C
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.6 Å
AuthorsOguma, T. / Asada, H. / Sekiguchi, Y. / Imono, M. / Iwata, S. / Kusakabe, K.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)22KK0099 Japan
CitationJournal: J.Med.Chem. / Year: 2024
Title: Dual 5-HT 2A and 5-HT 2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.
Authors: Oguma, T. / Jino, K. / Nakahara, K. / Asada, H. / Fuchino, K. / Nagatani, K. / Kouki, K. / Okamoto, R. / Takai, N. / Koda, K. / Fujita, S. / Sekiguchi, Y. / Yasuo, K. / Mayumi, K. / Abe, A. ...Authors: Oguma, T. / Jino, K. / Nakahara, K. / Asada, H. / Fuchino, K. / Nagatani, K. / Kouki, K. / Okamoto, R. / Takai, N. / Koda, K. / Fujita, S. / Sekiguchi, Y. / Yasuo, K. / Mayumi, K. / Abe, A. / Imono, M. / Horiguchi, N. / Iwata, S. / Kusakabe, K.I.
History
DepositionMay 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: 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 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2C,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,2242
Polymers49,7701
Non-polymers4541
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-4 kcal/mol
Surface area18430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.840, 96.010, 149.000
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number21
Space group name H-MC222
Space group name HallC22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z
#8: -x+1/2,-y+1/2,z

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Components

#1: Protein 5-hydroxytryptamine receptor 2C,Soluble cytochrome b562 / 5-HT-2C / 5-HT2C / 5-HTR2C / 5-hydroxytryptamine receptor 1C / 5-HT-1C / 5-HT1C / Serotonin ...5-HT-2C / 5-HT2C / 5-HTR2C / 5-hydroxytryptamine receptor 1C / 5-HT-1C / 5-HT1C / Serotonin receptor 2C / Cytochrome b-562


Mass: 49770.340 Da / Num. of mol.: 1 / Mutation: M29W,H124I,R128L,C360N
Source method: isolated from a genetically manipulated source
Details: the 243-300 aa region (ICL3) of 5-HT2c was replaced by imBRIL.
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: HTR2C, HTR1C, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28335, UniProt: P0ABE7
#2: Chemical ChemComp-A1L10 / 1-[(4-fluorophenyl)methyl]-1-[(8~{S})-5-methyl-5-azaspiro[2.5]octan-8-yl]-3-[[4-(2-methylpropoxy)phenyl]methyl]urea


Mass: 453.592 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H36FN3O2 / Feature type: SUBJECT OF INVESTIGATION
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: 3.24 Å3/Da / Density % sol: 62.01 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / Details: 18-24% PEG300, 40-60 mM ammonium phosphate dibasic / PH range: 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.6→49.07 Å / Num. obs: 7692 / % possible obs: 99.88 % / Redundancy: 38 % / Biso Wilson estimate: 73.5 Å2 / CC1/2: 0.995 / Rpim(I) all: 0.1738 / Net I/σ(I): 7.17
Reflection shellResolution: 3.6→3.83 Å / Num. unique obs: 1254 / CC1/2: 0.585 / Rpim(I) all: 0.7097

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Processing

Software
NameVersionClassification
PHENIX1.21_5207refinement
XSCALEdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BQH

6bqh


Resolution: 3.6→49.07 Å / SU ML: 0.5331 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.8439
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2854 780 10.15 %
Rwork0.2627 6904 -
obs0.2651 7684 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 83.45 Å2
Refinement stepCycle: LAST / Resolution: 3.6→49.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2652 0 33 0 2685
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00322745
X-RAY DIFFRACTIONf_angle_d0.71313733
X-RAY DIFFRACTIONf_chiral_restr0.0413444
X-RAY DIFFRACTIONf_plane_restr0.0065449
X-RAY DIFFRACTIONf_dihedral_angle_d15.1291992
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.6-3.830.33651260.30161128X-RAY DIFFRACTION100
3.83-4.120.27161220.26571141X-RAY DIFFRACTION100
4.12-4.530.28961360.2241115X-RAY DIFFRACTION100
4.54-5.190.26561260.26291143X-RAY DIFFRACTION99.76
5.19-6.530.34591310.29161166X-RAY DIFFRACTION99.92
6.54-49.070.25031390.25551211X-RAY DIFFRACTION99.63
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)
13.453767455441.953489070192.366758509796.506720020983.367564807012.386760755790.03900434763210.5603460144510.254030066421-0.1640933507710.329045275869-0.06037528534330.146266426362-0.01692762363590.01045340150090.358791171034-0.1416485967550.01792678760650.5795492858030.01751896168870.43281153871631.396212101545.359881279146.1612707488
22.05568955357-0.713678106289-0.03030877137212.18061847155-0.1893006957492.321195563390.07509424601830.534782441741-0.0650136187664-0.486290922749-0.0524774735673-0.1282951105060.3015914583620.192590793093-0.02617136416150.545080227927-0.164967198256-0.008342244805840.540280463936-0.02167208178610.48200126258638.417948907528.134130187844.1698476121
32.41070773619-0.468986563088-2.728342709487.9353528736-5.536131182727.78083255340.106660647413-0.335476582259-0.215970804196-1.36583569891-0.4294975380640.934939263443-0.6734363434640.634942620202-0.1951232229021.264253316590.0213982508318-0.330632324622.27398424532-0.398137337020.79579487773157.573620486927.74378014653.23861878475
43.3276516032-0.783494503185-1.115520199582.198340310820.2042675348784.865627166270.1094619836620.72562295998-0.218133743822-0.238174189698-0.135810150941-0.0348534913533-0.2170688046020.313990551627-0.2581722076890.437135665502-0.2327690911160.06421851312770.597292179471-0.03577356687540.42127153431343.944296461436.933500300541.3597235452
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 47 through 86 )47 - 861 - 40
22chain 'A' and (resid 87 through 1016 )87 - 101641 - 211
33chain 'A' and (resid 1017 through 1098 )1017 - 1098212 - 236
44chain 'A' and (resid 1099 through 387 )1099 - 387237 - 331

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