From Crystal Structures of RgIA4 in Complex with Ac-AChBP to Molecular Determinants of Its High Potency of α9α10 nAChR

Marine Drugs

Xinquan Wang¹  Si Pan²  Sulan Luo³  Xiaopeng Zhu³  Yi Xue⁴  Yingxu Fan⁴ 

[1] Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, The Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China;Key Laboratory of Translational Tumor Medicine in Fujian Province, Putian University, Putian 351100, China;Medical School, Guangxi University, Nanning 530004, China;Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China;

关键词: acetylcholine binding protein;    nicotinic acetylcholine receptors;    α-conotoxin;    RgIA;    RgIA4;    crystal structure;   

DOI  :  10.3390/md19120709

来源: DOAJ

【 摘 要 】

α9-containing nicotinic acetylcholine receptors (nAChRs) have been shown to play critical roles in neuropathic pain. The α-conotoxin (α-CTx) RgIA and its analog RgIA4 were identified as the most selective inhibitor of α9α10 nAChR. However, the mechanism of their selectivity toward α9α10 nAChR remains elusive. Here, we reported the co-crystal structure of RgIA and RgIA4 in complex with Aplysia californica acetylcholine binding protein (Ac-AChBP) at resolution of 2.6 Å, respectively. Based on the structure of the complexes, together with molecular dynamic simulation (MD-simulation), we suggested the key residues of α9α10 nAChR in determining its high affinity for RgIA/RgIA4. This is the first time the complex between pain-related conotoxins and Ac-AChBP was reported and the complementary side of α9 subunit in binding of the antagonists shown. These results provide realistic template for the design of new therapeutic in neuropathic pain.

【 授权许可】

Unknown