6DRZ

Structural Determinants of Activation and Biased Agonism at the 5-HT2B Receptor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural determinants of 5-HT2Breceptor activation and biased agonism.

McCorvy, J.D.Wacker, D.Wang, S.Agegnehu, B.Liu, J.Lansu, K.Tribo, A.R.Olsen, R.H.J.Che, T.Jin, J.Roth, B.L.

(2018) Nat Struct Mol Biol 25: 787-796

  • DOI: https://doi.org/10.1038/s41594-018-0116-7
  • Primary Citation of Related Structures:  
    6DRX, 6DRY, 6DRZ, 6DS0

  • PubMed Abstract: 

    Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor-the human 5-HT 2B receptor-in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.


  • Organizational Affiliation

    National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Chapel Hill Medical School, Chapel Hill, NC, USA. jmccorvy@mcw.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
5HT2B receptor, BRIL chimera411Homo sapiensEscherichia coliMutation(s): 3 
Gene Names: HTR2BcybC
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P41595 (Homo sapiens)
Explore P41595 
Go to UniProtKB:  P41595
PHAROS:  P41595
GTEx:  ENSG00000135914 
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0ABE7P41595
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 
B [auth A]CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
OLC
Query on OLC

Download Ideal Coordinates CCD File 
D [auth A](2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
H8J
Query on H8J

Download Ideal Coordinates CCD File 
G [auth A](8alpha)-N-[(2S)-1-hydroxybutan-2-yl]-1,6-dimethyl-9,10-didehydroergoline-8-carboxamide
C21 H27 N3 O2
KPJZHOPZRAFDTN-ZRGWGRIASA-N
OLA
Query on OLA

Download Ideal Coordinates CCD File 
C [auth A]OLEIC ACID
C18 H34 O2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
E [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
F [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.10 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.095α = 90
b = 119.283β = 90
c = 172.624γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesRO1MH61887
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesU19MH82441
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesR01NS100930
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesACB-12002
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesAGM-12006
Department of Energy (DOE, United States)United StatesDE-AC02-06CH11357

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-29
    Type: Initial release
  • Version 1.1: 2018-09-05
    Changes: Data collection, Database references
  • Version 1.2: 2018-09-19
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-11
    Changes: Data collection, Database references, Refinement description