2Y56: Fragment Growing Induces Conformational Changes In Acetylcholine-Binding Protein: A Structural And Thermodynamic Analysis - (Compound 3)

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.
PDB ID: 2Y56Download
MMDB ID: 91710
PDB Deposition Date: 2011/1/12
Updated in MMDB: 2011/07
Experimental Method:
x-ray diffraction
Resolution: 3.59  Å
Source Organism:
Similar Structures:
Biological Unit for 2Y56: pentameric; determined by author and by software (PISA)
Molecular Components in 2Y56
Label Count Molecule
Proteins (5 molecules)
Soluble Acetylcholine Receptor
Molecule annotation
Chemicals (39 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB