[English] 日本語
Yorodumi
- PDB-8zmf: Crystal structure of an inverse agonist antipsychotic drug deriva... -

+
Open data


ID or keywords:

Loading...

-
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 / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / regulation of appetite / G protein-coupled serotonin receptor complex / regulation of nervous system process / Serotonin receptors ...regulation of corticotropin-releasing hormone secretion / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / regulation of appetite / G protein-coupled serotonin receptor complex / regulation of nervous system process / Serotonin receptors / serotonin receptor signaling pathway / serotonin binding / G protein-coupled serotonin receptor activity / feeding behavior / neurotransmitter receptor activity / cGMP-mediated signaling / 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 / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more