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X-ray crystal structures of A\u0421hBP in complex with \u03b1-conotoxins provide important insights into the interactions of \u03b1-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why \u03b1-conotoxin GIC is strongly selective for \u03b13\u03b22 nAChR, this question has not yet been solved. Here we present the structure of \u03b1-conotoxin GIC in complex with <jats:italic>Aplysia californica<\/jats:italic> AChBP (<jats:italic>Ac<\/jats:italic>-AChBP) at a resolution of 2.1\u2009\u00c5. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human \u03b13\u03b22 vs \u03b13\u03b24 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with <jats:italic>Ac<\/jats:italic>-AChBP and \u03b13\u03b22 nAChR subtypes. While GIC elements responsible for its high affinity binding with <jats:italic>Ac<\/jats:italic>-AChBP and \u03b13\u03b22 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.<\/jats:p>","DOI":"10.1038\/srep22349","type":"journal-article","created":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T11:32:44Z","timestamp":1456831964000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["From crystal structure of \u03b1-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for \u03b13\u03b22 nAChR"],"prefix":"10.1038","volume":"6","author":[{"given":"Bo","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongting","family":"Zhangsun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-Hua","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor E.","family":"Kasheverov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor I.","family":"Tsetlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinquan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulan","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"BFsrep22349_CR1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/35077000","volume":"411","author":"AB Smit","year":"2001","unstructured":"Smit, A. 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