5XRA

Crystal structure of the human CB1 in complex with agonist AM11542


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.235 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Crystal structures of agonist-bound human cannabinoid receptor CB1

Hua, T.Vemuri, K.Nikas, S.P.Laprairie, R.B.Wu, Y.Qu, L.Pu, M.Korde, A.Jiang, S.Ho, J.H.Han, G.W.Ding, K.Li, X.Liu, H.Hanson, M.A.Zhao, S.Bohn, L.M.Makriyannis, A.Stevens, R.C.Liu, Z.J.

(2017) Nature 547: 468-471

  • DOI: https://doi.org/10.1038/nature23272
  • Primary Citation of Related Structures:  
    5XR8, 5XRA

  • PubMed Abstract: 

    The cannabinoid receptor 1 (CB 1 ) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB 1 -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe200 3.36 and Trp356 6.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB 1 and provide a molecular basis for predicting the binding modes of Δ 9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.


  • Organizational Affiliation

    iHuman Institute, ShanghaiTech University, Shanghai 201210, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cannabinoid receptor 1,Flavodoxin,Cannabinoid receptor 1438Homo sapiensNitratidesulfovibrio vulgaris str. HildenboroughMutation(s): 5 
Gene Names: CNR1CNRDVU_2680
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P00323 (Desulfovibrio vulgaris (strain ATCC 29579 / DSM 644 / NCIMB 8303 / VKM B-1760 / Hildenborough))
Explore P00323 
Go to UniProtKB:  P00323
Find proteins for P21554 (Homo sapiens)
Explore P21554 
Go to UniProtKB:  P21554
PHAROS:  P21554
GTEx:  ENSG00000118432 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00323P21554
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMN
Query on FMN

Download Ideal Coordinates CCD File 
B [auth A]FLAVIN MONONUCLEOTIDE
C17 H21 N4 O9 P
FVTCRASFADXXNN-SCRDCRAPSA-N
8D3
Query on 8D3

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C [auth A](6aR,10aR)-3-(8-bromanyl-2-methyl-octan-2-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol
C25 H37 Br O2
SZDVFUZKFPGYEK-WOJBJXKFSA-N
CLR
Query on CLR

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I [auth A]CHOLESTEROL
C27 H46 O
HVYWMOMLDIMFJA-DPAQBDIFSA-N
OLC
Query on OLC

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F [auth A],
G [auth A]
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
OLA
Query on OLA

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D [auth A],
E [auth A]
OLEIC ACID
C18 H34 O2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N
PEG
Query on PEG

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H [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.235 
  • Space Group: P 21 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.05α = 90
b = 75.87β = 90
c = 138.9γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2017-07-12
    Type: Initial release
  • Version 1.1: 2017-07-19
    Changes: Database references
  • Version 1.2: 2017-08-09
    Changes: Database references
  • Version 1.3: 2017-08-16
    Changes: Data collection, Refinement description
  • Version 1.4: 2017-10-18
    Changes: Author supporting evidence
  • Version 1.5: 2023-11-22
    Changes: Data collection, Database references, Refinement description