6A94

Crystal structure of 5-HT2AR in complex with zotepine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.238 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structures of the 5-HT2Areceptor in complex with the antipsychotics risperidone and zotepine.

Kimura, K.T.Asada, H.Inoue, A.Kadji, F.M.N.Im, D.Mori, C.Arakawa, T.Hirata, K.Nomura, Y.Nomura, N.Aoki, J.Iwata, S.Shimamura, T.

(2019) Nat Struct Mol Biol 26: 121-128

  • DOI: https://doi.org/10.1038/s41594-018-0180-z
  • Primary Citation of Related Structures:  
    6A93, 6A94

  • PubMed Abstract: 

    Many drugs target the serotonin 2A receptor (5-HT 2A R), including second-generation antipsychotics that also target the dopamine D 2 receptor (D 2 R). These drugs often produce severe side effects due to non-selective binding to other aminergic receptors. Here, we report the structures of human 5-HT 2A R in complex with the second-generation antipsychotics risperidone and zotepine. These antipsychotics effectively stabilize the inactive conformation by forming direct contacts with the residues at the bottom of the ligand-binding pocket, the movements of which are important for receptor activation. 5-HT 2A R is structurally similar to 5-HT 2C R but possesses a unique side-extended cavity near the orthosteric binding site. A docking study and mutagenic studies suggest that a highly 5-HT 2A R-selective antagonist binds the side-extended cavity. The conformation of the ligand-binding pocket in 5-HT 2A R significantly differs around extracellular loops 1 and 2 from that in D 2 R. These findings are beneficial for the rational design of safer antipsychotics and 5-HT 2A R-selective drugs.


  • Organizational Affiliation

    Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
A, B
376Homo sapiensEscherichia coliMutation(s): 6 
Gene Names: HTR2AHTR2cybC
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P28223 (Homo sapiens)
Explore P28223 
Go to UniProtKB:  P28223
PHAROS:  P28223
GTEx:  ENSG00000102468 
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP28223P0ABE7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CLR
Query on CLR

Download Ideal Coordinates CCD File 
D [auth A],
I [auth B]
CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
A6L
Query on A6L

Download Ideal Coordinates CCD File 
J [auth B]2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-KTKRTIGZSA-N
ZOT
Query on ZOT

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
2-(3-chloranylbenzo[b][1]benzothiepin-5-yl)oxy-N,N-dimethyl-ethanamine
C18 H18 Cl N O S
HDOZVRUNCMBHFH-UHFFFAOYSA-N
PLM
Query on PLM

Download Ideal Coordinates CCD File 
H [auth B]PALMITIC ACID
C16 H32 O2
IPCSVZSSVZVIGE-UHFFFAOYSA-N
1PE
Query on 1PE

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E [auth A]PENTAETHYLENE GLYCOL
C10 H22 O6
JLFNLZLINWHATN-UHFFFAOYSA-N
ZN
Query on ZN

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F [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.238 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 279.18α = 90
b = 42.22β = 92.16
c = 91.71γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-02-13
    Type: Initial release
  • Version 1.1: 2019-11-20
    Changes: Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Derived calculations, Refinement description