3U8J

Crystal structure of the acetylcholine binding protein (AChBP) from Lymnaea stagnalis in complex with NS3531 (1-(pyridin-3-yl)-1,4-diazepane)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha 4 beta 2 receptors: unique role of halogen bonding revealed.

Rohde, L.A.Ahring, P.K.Jensen, M.L.Nielsen, E.Peters, D.Helgstrand, C.Krintel, C.Harpse, K.Gajhede, M.Kastrup, J.S.Balle, T.

(2012) J Biol Chem 287: 4248-4259

  • DOI: https://doi.org/10.1074/jbc.M111.292243
  • Primary Citation of Related Structures:  
    3U8J, 3U8K, 3U8L, 3U8M, 3U8N

  • PubMed Abstract: 

    The α4β2 subtype of the nicotinic acetylcholine receptor has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of α4β2 agonists is lacking. Using binding experiments, electrophysiology and x-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at α4β2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for α4β2 receptors. Crystal structures of five agonists with efficacies at α4β2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong intersubunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong intersubunit anchoring.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholine-binding protein210Lymnaea stagnalisMutation(s): 0 
UniProt
Find proteins for P58154 (Lymnaea stagnalis)
Explore P58154 
Go to UniProtKB:  P58154
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP58154
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
W [auth G]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
09O
Query on 09O

Download Ideal Coordinates CCD File 
K [auth B]
M [auth A]
P [auth C]
Q [auth D]
S [auth E]
K [auth B],
M [auth A],
P [auth C],
Q [auth D],
S [auth E],
T [auth F],
U [auth G],
X [auth J],
Y [auth I],
Z [auth H]
1-(pyridin-3-yl)-1,4-diazepane
C10 H15 N3
JBOVXXZNZSULJJ-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth H]
L [auth B]
N [auth A]
O [auth A]
R [auth E]
AA [auth H],
L [auth B],
N [auth A],
O [auth A],
R [auth E],
V [auth G]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
09O BindingDB:  3U8J Ki: 3.1 (nM) from 1 assay(s)
PDBBind:  3U8J Ki: 3.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.205 
  • R-Value Observed: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.35α = 90
b = 114.43β = 90
c = 247.37γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
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: 2011-12-14
    Type: Initial release
  • Version 1.1: 2013-09-18
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Refinement description, Structure summary