2Y57

Fragment growing induces conformational changes in acetylcholine- binding protein: A structural and thermodynamic analysis - (Compound 4)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Fragment Growing Induces Conformational Changes in Acetylcholine-Binding Protein: A Structural and Thermodynamic Analysis.

Edink, E.Rucktooa, P.Retra, K.Akdemir, A.Nahar, T.Zuiderveld, O.Van Elk, R.Janssen, E.Van Nierop, P.Van Muijlwijk-Koezen, J.Smit, A.B.Sixma, T.K.Leurs, R.De Esch, I.J.P.

(2011) J Am Chem Soc 133: 5363

  • DOI: https://doi.org/10.1021/ja110571r
  • Primary Citation of Related Structures:  
    2Y54, 2Y56, 2Y57, 2Y58

  • PubMed Abstract: 

    Optimization of fragment hits toward high-affinity lead compounds is a crucial aspect of fragment-based drug discovery (FBDD). In the current study, we have successfully optimized a fragment by growing into a ligand-inducible subpocket of the binding site of acetylcholine-binding protein (AChBP). This protein is a soluble homologue of the ligand binding domain (LBD) of Cys-loop receptors. The fragment optimization was monitored with X-ray structures of ligand complexes and systematic thermodynamic analyses using surface plasmon resonance (SPR) biosensor analysis and isothermal titration calorimetry (ITC). Using site-directed mutagenesis and AChBP from different species, we find that specific changes in thermodynamic binding profiles, are indicative of interactions with the ligand-inducible subpocket of AChBP. This study illustrates that thermodynamic analysis provides valuable information on ligand binding modes and is complementary to affinity data when guiding rational structure- and fragment-based discovery approaches.


  • Organizational Affiliation

    Leiden/Amsterdam Center of Drug Research (LACDR), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SOLUBLE ACETYLCHOLINE RECEPTOR
A, B, C, D, E
217Aplysia californicaMutation(s): 0 
UniProt
Find proteins for Q8WSF8 (Aplysia californica)
Explore Q8WSF8 
Go to UniProtKB:  Q8WSF8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8WSF8
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V37
Query on V37

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
N [auth C],
Q [auth D],
T [auth E]
[(1R,5S)-8-PHENETHYL-8-AZABICYCLO[3.2.1]OCTAN-3-YL] BENZOATE
C22 H25 N O2
ZVQCTZVWEBSXKK-AERCQKQUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
H [auth A]
I [auth A]
L [auth B]
M [auth B]
P [auth C]
H [auth A],
I [auth A],
L [auth B],
M [auth B],
P [auth C],
S [auth D],
V [auth E],
W [auth E]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
O [auth C],
R [auth D],
U [auth E]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
V37 BindingDB:  2Y57 Ki: 31.62 (nM) from 1 assay(s)
PDBBind:  2Y57 Kd: 130 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.30 Å
  • R-Value Free: 0.193 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 210.74α = 90
b = 210.74β = 90
c = 210.74γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
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: 2011-06-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2019-04-24
    Changes: Data collection, Other, Source and taxonomy
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description