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

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    High Selectivity of an α-Conotoxin LvIA Analogue for α3β2 Nicotinic Acetylcholine Receptors Is Mediated by β2 Functionally Important Residues
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    • Xiaopeng Zhu
      Xiaopeng Zhu
      Medical School, Guangxi University, Nanning 530004, China
      Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China
      More by Xiaopeng Zhu
      Orcidhttp://orcid.org/0000-0001-8830-4954
    • Si Pan
      Si Pan
      The Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
      More by Si Pan
    • Manyu Xu
      Manyu Xu
      The Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
      More by Manyu Xu
    • Lu Zhang
      Lu Zhang
      Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China
      More by Lu Zhang
    • Jinfang Yu
      Jinfang Yu
      The Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
      More by Jinfang Yu
    • Jinpeng Yu
      Jinpeng Yu
      Medical School, Guangxi University, Nanning 530004, China
      More by Jinpeng Yu
    • Yong Wu
      Yong Wu
      Medical School, Guangxi University, Nanning 530004, China
      More by Yong Wu
    • Yingxu Fan
      Yingxu Fan
      Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
      More by Yingxu Fan
    • Haonan Li
      Haonan Li
      Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China
      More by Haonan Li
    • Igor E. Kasheverov
      Igor E. Kasheverov
      Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, Moscow 117997, Russia
      Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Trubetskaya Street 8, bld. 2, Moscow 119991, Russia
      More by Igor E. Kasheverov
    • Denis S. Kudryavtsev
      Denis S. Kudryavtsev
      Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, Moscow 117997, Russia
      More by Denis S. Kudryavtsev
    • Victor I. Tsetlin
      Victor I. Tsetlin
      Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, Moscow 117997, Russia
      PhysBio of MePhi, Kashirskoe Ave. 31, Moscow 115409, Russia
      More by Victor I. Tsetlin
    • Yi Xue
      Yi Xue
      Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
      More by Yi Xue
    • Dongting Zhangsun
      Dongting Zhangsun
      Medical School, Guangxi University, Nanning 530004, China
      Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China
      More by Dongting Zhangsun
    • Xinquan Wang*
      Xinquan Wang
      The Ministry of Education Key Laboratory of Protein Science, School of Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Biotherapy, Tsinghua University, Beijing 100084, China
      *Email: [email protected]
      More by Xinquan Wang
    • Sulan Luo*
      Sulan Luo
      Medical School, Guangxi University, Nanning 530004, China
      Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China
      *Email: [email protected]
      More by Sulan Luo
      Orcidhttp://orcid.org/0000-0002-3568-5797
    Other Access OptionsSupporting Information (3)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 22, 13656–13668
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.0c00975
    Published November 16, 2020
    Copyright © 2020 American Chemical Society
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    Abstract

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    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.

    Copyright © 2020 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00975.

    • HPLC and mass spectra profile of α-conotoxin LvIA analogues (Figure S1), three LvIA analogues having no potency for rat α3β2 and α3β4 nAChRs (Figure S2), bar presentation of the change in the potency of each analogue of α-conotoxin LvIA for Ac-AChBP (Figure S3), [N9A]LvIA blocking the rat α3β2[S168I] nAChR mutant (Figure S4), amino acid residues between α-CTx and Ac-AChBP with a distance cutoff of 4.0 Å (Table S1), modeled contacts of α-CTxs [N9A]LvIA and [D11A]LvIA with rα3β2 and rα3β4, respectively (Table S2), sequences of primers used to construct point mutants (Table S3), and data collection and refinement statistics (Table S4) (PDF)

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    • Crystallographic data (ZIP)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 22, 13656–13668
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.0c00975
    Published November 16, 2020
    Copyright © 2020 American Chemical Society
    Request reuse permissions

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