2W8G

Aplysia californica AChBP bound to in silico compound 35

Summary for 2W8G

• Entry DOI: 10.2210/pdb2w8g/pdb
• Related: 2BR7 2BR8 2BYN 2BYP 2BYQ 2BYR 2BYS 2C9T 2UZ6 2W8E 2W8F
• Descriptor: SOLUBLE ACETYLCHOLINE RECEPTOR, (3-ENDO,8-ANTI)-8-BENZYL-3-(10,11-DIHYDRO-5H-DIBENZO[A,D][7]ANNULEN-5-YLOXY)-8-AZONIABICYCLO[3.2.1]OCTANE (3 entities in total)
• Functional Keywords: receptor, acetylcholine receptor inhibitor, postsynaptic neurotoxin, toxin, secreted, amidation, conotoxin, neurotoxin, acetylcholine binding protein, nicotinic acetylcholine receptor-toxin complex, cleavage on pair of basic residues, conformational flexibility
• Biological source: APLYSIA CALIFORNICA (CALIFORNIA SEA HARE)
• Total number of polymer chains: 5
• Total formula weight: 124674.60

Authors

Ulens, C.,Akdemir, A.,Jongejan, A.,van Elk, R.,Edink, E.,Bertrand, S.,Perrakis, A.,Leurs, R.,Smit, A.B.,Sixma, T.K.,Bertrand, D.,de Esch, I.J. (deposition date: 2009-01-16, release date: 2009-04-14, Last modification date: 2024-10-23)

Primary citation

Ulens, C.,Akdemir, A.,Jongejan, A.,Van Elk, R.,Bertrand, S.,Perrakis, A.,Leurs, R.,Smit, A.B.,Sixma, T.K.,Bertrand, D.,De Esch, I.J.
Use of Acetylcholine Binding Protein in the Search for Novel Alpha7 Nicotinic Receptor Ligands. In Silico Docking, Pharmacological Screening, and X- Ray Analysis.
J.Med.Chem., 52:2372-, 2009

PubMed Abstract: Acetylcholine binding protein (AChBP) is widely considered as a functional and structural homologue of the ligand binding domain of Cys-loop receptors. We report the use of AChBP as template to identify ligands for the nicotinic receptors (nAChRs). An in silico screening protocol was set up and applied to crystal structures of AChBP. Several ligands containing a dibenzosuberyl moiety were identified and shown to bind with high affinity to AChBP and alpha7 nAChRs. Two high affinity ligands were cocrystallized with AChBP, revealing the binding mode in the orthosteric site. Functional studies revealed that these two ligands caused inhibition of the alpha7, alpha4beta2, and 5HT(3) receptors. The noncompetive blockade of the receptors suggests that these compounds act by steric hindrance of the channel. The analysis of the dual binding mode of these dibenzosuberyl-containing compounds can lead to better understanding of the complex mode of action of similar tricyclic ligands on Cys-loop receptors.

PubMed: 19331415
DOI: 10.1021/JM801400G

Experimental method

X-RAY DIFFRACTION (2.6 Å)