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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Molecular dynamics simulations revealed a gating mechanism of nicotinic acetylcholine receptors

2019년 8월 26일 11시 29분 26초
LIFE.P-223 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 18일 (금요일) 11:00~12:30
Life Chemistry
저자 및
Myunggi Yi
Department of Biomedical Engineering, Pukyong National University, Korea
Nicotinic acetylcholine receptors (nAChR) are essential in neurotransmission. Although there are many research on the allosteric mechanism of ligand binding event triggering channel opening in transmembrane domain, the relationship between structure and function in atomic scale is still unclear. In this study, we focused on investigating the gating mechanism of nAChR through either apo form or ligand bound forms. We performed 4 molecular dynamics (MD) simulations of α4β2 nAChR: wild type of apo form (APO), acetylcholine bound wild type (ACH), wild type of BuIA toxin bound form (WT) and toxin bound mutant type (MT) α4β2 nAChR’s whose 3 residues of α4 subunit (Tyr185, 187Asp and Agr188) replaced by 3 corresponding residues of α6 subunit. These three α6 residues are determinants of the toxin α-conotoxin BuIA selectivity of α6 subunit. The calculations of pore radii of the channels showed that the MT and APO forms had restriction radii of 1.9 and 2.3 Å (Glu261, Lys260 on beta subunit), while the same region was broadened in WT and in ACH (radii of 2.6 and 3.4 Å). The analysis of conformations showed that the asymmetric tilting motion of extra cellular domain (ECD) was observed in WT and ACH caused the asymmetric twist angle between ECD and TMD. This motion induced the asymmetrically arranged transmembrane domain (TMD) to become more symmetric. In contract, the opposite tendency was observed in MT and APO systems. In summary, we conclude that the inherent asymmetric arrangement of α4β2 nAChR can be broken by an unequally tilting motion of ECD and induce the symmetric arrangement in TMD, which makes the channel open.