High Selectivity of an α-Conotoxin LvIA Analogue for α3β2 Nicotinic Acetylcholine Receptors Is Mediated by β2 Functionally Important Residues

Journal of Medicinal Chemistry
Xiaopeng ZhuSulan Luo

Abstract

The α3β2 and α3β4 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central and peripheral nervous systems, playing critical roles in various physiological processes and in such pathologies as addiction to nicotine and other drugs of abuse. α-Conotoxin LvIA, which we previously isolated from Conus lividus, modestly discriminates α3β2 and α3β4 rat nAChRs exhibiting a ∼17-fold tighter binding to the former. Here, alanine scanning resulted in two more selective analogues [N9A]LvIA and [D11A]LvIA, the former having a >2000-fold higher selectivity for α3β2. The determined crystal structures of [N9A]LvIA and [D11A]LvIA bound to the acetylcholine-binding protein (AChBP) were followed by homologous modeling of the complexes with the α3β2 and α3β4 nAChRs and by receptor mutagenesis, which revealed Phe106, Ser108, Ser113, and Ser168 residues in the β2 subunit as essential for LvIA binding. These results may be useful for the design of novel compounds of therapeutic potential targeting α3β2 nAChRs.

References

Nov 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·J BoulterJ Patrick
Mar 1, 1993·Experimental Cell Research·G Almouzni, A P Wolffe
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·P J CorringerJ P Changeux
Aug 17, 2002·The Journal of Pharmacology and Experimental Therapeutics·Xiaoping ZhouJames J Galligan
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
May 29, 2003·Current Drug Targets. CNS and Neurological Disorders·Mariella De Biasi
Mar 27, 2004·Molecular Pharmacology·J Michael McIntoshPaul Whiteaker
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jun 14, 2005·Nature Structural & Molecular Biology·Patrick H N CelieAugust B Smit
Mar 1, 2006·Proceedings of the National Academy of Sciences of the United States of America·Chris UlensTitia K Sixma
Nov 15, 2006·Proceedings of the National Academy of Sciences of the United States of America·Michelle VinclerJ Michael McIntosh
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoy
Aug 30, 2008·Neuropharmacology·Neil S Millar, Cecilia Gotti
May 19, 2009·Acta Pharmacologica Sinica·Layla Azam, J Michael McIntosh
Feb 11, 2010·The Journal of Biological Chemistry·Sulan LuoJ Michael McIntosh
Mar 13, 2012·Pharmacological Reviews·Richard J LewisMacDonald J Christie
Jan 9, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sulan LuoPaul Whiteaker
Apr 12, 2014·Chemical Reviews·Kalyana B AkondiPaul F Alewood
Nov 21, 2014·The Journal of Biological Chemistry·Shiva N KompellaDavid J Adams
Dec 3, 2014·Neuropharmacology·Michele ZoliCecilia Gotti
Feb 26, 2015·The Journal of Biological Chemistry·Dongting ZhangsunSulan Luo
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Sep 10, 2013·Journal of Chemical Theory and Computation·Romelia Salomon-FerrerRoss C Walker
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor
Aug 10, 2017·Pflügers Archiv : European journal of physiology·Manuel Criado

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