2Y54

Fragment growing induces conformational changes in acetylcholine- binding protein: A structural and thermodynamic analysis - (Fragment 1)

Summary for 2Y54

• Entry DOI: 10.2210/pdb2y54/pdb
• Related: 2BR7 2BR8 2BYN 2BYP 2BYQ 2BYR 2BYS 2C9T 2UZ6 2W8E 2W8F 2W8G 2WN9 2WNC 2WNJ 2WNL 2WZY 2X00 2XNT 2XNU 2XNV 2XYS 2XYT 2XZ5 2XZ6 2Y56 2Y57 2Y58
• Descriptor: SOLUBLE ACETYLCHOLINE RECEPTOR, [(1R,5S)-8-AZABICYCLO[3.2.1]OCTAN-3-YL] BENZOATE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: receptor
• Biological source: APLYSIA CALIFORNICA (CALIFORNIA SEA HARE)
• Total number of polymer chains: 5
• Total formula weight: 125004.18

Authors

Rucktooa, P.,Edink, E.,deEsch, I.J.P.,Sixma, T.K. (deposition date: 2011-01-12, release date: 2011-06-15, Last modification date: 2024-10-16)

Primary citation

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.
Fragment Growing Induces Conformational Changes in Acetylcholine-Binding Protein: A Structural and Thermodynamic Analysis.
J.Am.Chem.Soc., 133:5363-, 2011

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.

PubMed: 21322593
DOI: 10.1021/JA110571R

Experimental method

X-RAY DIFFRACTION (3.65 Å)