Solution structure of α-conotoxin PIA, a novel antagonist of α6 subunit containing nicotinic acetylcholine receptors =니코틴 아세틸콜린 수용체 알파6에 특이적 저해제인 알파코노톡신 PIA의 구조

Abstract

α-Conotoxin PIA is a novel nicotinic acetylcholine receptor (nAChR) antagonist isolated from Conus purpurascens that targets nAChR subtypes containing α6 and α3 subunits. α-conotoxin PIA displays 75-fold higher affinity for rat α6/α3β2β3 nAChRs than for rat α3β2 nAChRs. We have determined the three-dimensional structure of α-conotoxin PIA by nuclear magnetic resonance spectroscopy. The α-conotoxin PIA has an "ω-shaped" overall topology as other α4/7 subfamily conotoxins. Yet, unlike other neuronally targeted α4/7-conotoxins, its N-terminal tail Arg1-Asp 2-Pro3 protrudes out of its main molecular body because Asp2-Pro3-Cys4-Cys5 forms a stable type I β-turn. In addition, a kink introduced by Pro15 in the second loop of this toxin provides a distinct steric and electrostatic environment from those in α-conotoxins MII and GIC. By comparing the structure of α-conotoxin PIA with other functionally related α-conotoxins we suggest structural features in α-conotoxin PIA that may be associated with its unique receptor recognition profile.