5DSG

Structure of the M4 muscarinic acetylcholine receptor (M4-mT4L) bound to tiotropium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.228 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.

Thal, D.M.Sun, B.Feng, D.Nawaratne, V.Leach, K.Felder, C.C.Bures, M.G.Evans, D.A.Weis, W.I.Bachhawat, P.Kobilka, T.S.Sexton, P.M.Kobilka, B.K.Christopoulos, A.

(2016) Nature 531: 335-340

  • DOI: https://doi.org/10.1038/nature17188
  • Primary Citation of Related Structures:  
    5CXV, 5DSG

  • PubMed Abstract: 

    Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.


  • Organizational Affiliation

    Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Muscarinic acetylcholine receptor M4,Endolysin,Endolysin,Muscarinic acetylcholine receptor M4
A, B
422Homo sapiensTequatrovirus T4Mutation(s): 2 
Gene Names: CHRM4
EC: 3.2.1.17
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P08173 (Homo sapiens)
Explore P08173 
Go to UniProtKB:  P08173
PHAROS:  P08173
GTEx:  ENSG00000180720 
Find proteins for P00720 (Enterobacteria phage T4)
Explore P00720 
Go to UniProtKB:  P00720
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP00720P08173
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0HK
Query on 0HK

Download Ideal Coordinates CCD File 
C [auth A],
L [auth B]
(1R,2R,4S,5S,7S)-7-{[hydroxy(dithiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0~2,4~]nonane
C19 H22 N O4 S2
LERNTVKEWCAPOY-DZZGSBJMSA-N
OLC
Query on OLC

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A],
J [auth A],
M [auth B],
Q [auth B]
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
C21 H40 O4
RZRNAYUHWVFMIP-GDCKJWNLSA-N
EDT
Query on EDT

Download Ideal Coordinates CCD File 
F [auth A]{[-(BIS-CARBOXYMETHYL-AMINO)-ETHYL]-CARBOXYMETHYL-AMINO}-ACETIC ACID
C10 H16 N2 O8
KCXVZYZYPLLWCC-UHFFFAOYSA-N
OLA
Query on OLA

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
K [auth A],
N [auth B],
O [auth B]
OLEIC ACID
C18 H34 O2
ZQPPMHVWECSIRJ-KTKRTIGZSA-N
P6G
Query on P6G

Download Ideal Coordinates CCD File 
G [auth A],
P [auth B]
HEXAETHYLENE GLYCOL
C12 H26 O7
IIRDTKBZINWQAW-UHFFFAOYSA-N
PG6
Query on PG6

Download Ideal Coordinates CCD File 
R [auth B]1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE
C12 H26 O6
DMDPGPKXQDIQQG-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.228 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.49α = 90
b = 172.04β = 94.37
c = 60.66γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
Aimlessdata scaling
PHASERphasing
Cootmodel building
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)AustraliaAPP1055134

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-16
    Type: Initial release
  • Version 1.1: 2016-03-23
    Changes: Database references
  • Version 1.2: 2016-03-30
    Changes: Database references
  • Version 1.3: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations, Refinement description
  • Version 1.4: 2017-10-11
    Changes: Data collection
  • Version 1.5: 2020-01-08
    Changes: Author supporting evidence
  • Version 1.6: 2024-03-13
    Changes: Data collection, Database references, Source and taxonomy