7E33

Serotonin 1E (5-HT1E) receptor-Gi protein complex


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.90 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Structural insights into the lipid and ligand regulation of serotonin receptors.

Xu, P.Huang, S.Zhang, H.Mao, C.Zhou, X.E.Cheng, X.Simon, I.A.Shen, D.D.Yen, H.Y.Robinson, C.V.Harpsoe, K.Svensson, B.Guo, J.Jiang, H.Gloriam, D.E.Melcher, K.Jiang, Y.Zhang, Y.Xu, H.E.

(2021) Nature 592: 469-473

  • DOI: https://doi.org/10.1038/s41586-021-03376-8
  • Primary Citation of Related Structures:  
    7E2X, 7E2Y, 7E2Z, 7E32, 7E33

  • PubMed Abstract: 

    Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter 1,2 that activates the largest subtype family of G-protein-coupled receptors 3 . Drugs that target 5-HT 1A , 5-HT 1D , 5-HT 1E and other 5-HT receptors are used to treat numerous disorders 4 . 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT 1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT 1D bound to 5-HT; and 5-HT 1E in complex with a 5-HT 1E - and 5-HT 1F -selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT 1A interface, and is able to increase 5-HT 1A -mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT 1A , in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT 1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.


  • Organizational Affiliation

    Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(i) subunit alpha-1354Homo sapiensMutation(s): 4 
Gene Names: GNAI1
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P63096 (Homo sapiens)
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Go to UniProtKB:  P63096
PHAROS:  P63096
GTEx:  ENSG00000127955 
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UniProt GroupP63096
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1345Homo sapiensMutation(s): 0 
Gene Names: GNB1
UniProt & NIH Common Fund Data Resources
Find proteins for P62873 (Homo sapiens)
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Go to UniProtKB:  P62873
PHAROS:  P62873
GTEx:  ENSG00000078369 
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UniProt GroupP62873
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
scFv16C [auth E]248Mus musculusMutation(s): 0 
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2D [auth G]71Homo sapiensMutation(s): 0 
Gene Names: GNG2
Membrane Entity: Yes 
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Find proteins for P59768 (Homo sapiens)
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PHAROS:  P59768
GTEx:  ENSG00000186469 
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UniProt GroupP59768
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  • Reference Sequence
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Soluble cytochrome b562,5-hydroxytryptamine receptor 1EE [auth R]504Escherichia coliHomo sapiens
This entity is chimeric
Mutation(s): 4 
Gene Names: cybCHTR1E
Membrane Entity: Yes 
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Find proteins for P28566 (Homo sapiens)
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Go to UniProtKB:  P28566
PHAROS:  P28566
GTEx:  ENSG00000168830 
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Entity Groups  
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UniProt GroupsP0ABE7P28566
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HVU (Subject of Investigation/LOI)
Query on HVU

Download Ideal Coordinates CCD File 
F [auth R]3-(1-methylpiperidin-4-yl)-1H-indol-5-ol
C14 H18 N2 O
WKNFADCGOAHBPG-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.90 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of China (NSFC)China31770796

Revision History  (Full details and data files)

  • Version 1.0: 2021-04-14
    Type: Initial release
  • Version 1.1: 2021-04-28
    Changes: Database references