{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T11:55:56Z","timestamp":1782561356837,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81473192"],"award-info":[{"award-number":["81473192"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>\u03b1-conotoxin AuIB is the only one of the 4\/6 type \u03b1-conotoxins (\u03b1-CTxs) that inhibits the \u03b3-aminobutyric acid receptor B (GABABR)-coupled N-type calcium channel (CaV2.2). To improve its inhibitory activity, a series of variants were synthesized and evaluated according to the structure\u2013activity relationships of 4\/7 type \u03b1-CTxs targeting GABABR-coupled CaV2.2. Surprisingly, only the substitution of Pro7 with Arg results in a 2\u20133-fold increase in the inhibition of GABABR-coupled CaV2.2 (IC50 is 0.74 nM); substitutions of position 9\u201312 with basic or hydrophobic amino acid and the addition of hydrophobic amino acid Leu or Ile at the second loop to mimic 4\/7 type \u03b1-CTxs all failed to improve the inhibitory activity of AuIB against GABABR-coupled CaV2.2. Interestingly, the most potent form of AuIB[P7R] has disulfide bridges of \u201c1\u20134, 2\u20133\u201d (ribbon), which differs from the \u201c1\u20133, 2\u20134\u201d (globular) in the isoforms of wildtype AuIB. In addition, AuIB[P7R](globular) displays potent analgesic activity in the acetic acid writhing model and the partial sciatic nerve injury (PNL) model. Our study demonstrated that 4\/6 type \u03b1-CTxs, with the disulfide bridge connectivity \u201c1\u20134, 2\u20133,\u201d are also potent inhibitors for GABABR-coupled CaV2.2, exhibiting potent analgesic activity.<\/jats:p>","DOI":"10.3390\/md20120750","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T02:09:58Z","timestamp":1669687798000},"page":"750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Single Amino Acid Replacement Boosts the Analgesic Activity of \u03b1-Conotoxin AuIB through the Inhibition of the GABABR-Coupled N-Type Calcium Channel"],"prefix":"10.3390","volume":"20","author":[{"given":"Yuanmei","family":"Wei","sequence":"first","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"},{"name":"Institute of Snake Venom, School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Yu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfang","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Xu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Huang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhou","family":"Yu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Snake Venom, School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2062-8332","authenticated-orcid":false,"given":"Qiuyun","family":"Dai","sequence":"additional","affiliation":[{"name":"Beijing Institute of Biotechnology, Beijing 100071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.3390\/md12052970","article-title":"Conotoxins targeting nicotinic acetylcholine receptors: An overview","volume":"12","author":"Lebbe","year":"2014","journal-title":"Mar. 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