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The tetraspanin CD81 is an essential entry-level receptor required for HCV infection of hepatocytes and represents a critical target for intervention. In this study, we report the first structural characterization of the large extracellular loop of CD81, expressed in mammalian cells and studied in physiological solutions. The HCV E2 glycoprotein recognizes CD81 through a dynamic loop on the helical bundle, which was shown by nuclear magnetic resonance (NMR) spectroscopy to adopt a conformation distinct from that seen in crystals. A novel membrane binding interface was revealed adjacent to the exposed HCV interaction site in the extracellular loop of CD81. The binding pockets for two proposed inhibitors of the CD81-HCV interaction, namely, benzyl salicylate and fexofenadine, were shown to overlap the HCV and membrane interaction sites. Although the dynamic loop region targeted by these compounds presents challenges for structure-based design, the NMR assignments enable realistic screening and validation of ligands. Together, these data provide an improved avenue for developing potent agents that specifically block CD81-HCV interaction and also pave a way for elucidating the recognition mechanisms of diverse tetraspanins.<\/jats:p>","DOI":"10.1128\/jvi.00559-12","type":"journal-article","created":{"date-parts":[[2012,6,28]],"date-time":"2012-06-28T03:47:43Z","timestamp":1340855263000},"page":"9606-9616","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":56,"title":["Structural Basis of Ligand Interactions of the Large Extracellular Domain of Tetraspanin CD81"],"prefix":"10.1128","volume":"86","author":[{"given":"Sundaresan","family":"Rajesh","sequence":"first","affiliation":[{"name":"School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Sridhar","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birke Andrea","family":"Tews","sequence":"additional","affiliation":[{"name":"Center for Infection and Immunity of Lille, University Lille Nord de France, CNRS UMR8204, INSERM U1019, Pasteur Institute of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"F\u00e9n\u00e9ant","sequence":"additional","affiliation":[{"name":"Center for Infection and Immunity of Lille, University Lille Nord de France, CNRS UMR8204, INSERM U1019, Pasteur Institute of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Cocquerel","sequence":"additional","affiliation":[{"name":"Center for Infection and Immunity of Lille, University Lille Nord de France, CNRS UMR8204, INSERM U1019, Pasteur Institute of Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas G.","family":"Ward","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedor","family":"Berditchevski","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Overduin","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01573-06"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02170-10"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444906029799"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001086"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2030692"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-007-9208-0"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.10.4940-4948.2006"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.4049\/jimmunol.149.9.2841","article-title":"The CD19\/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules","volume":"149","author":"Bradbury L","year":"1992","unstructured":"BradburyL KansasG LevyS EvansR TedderT. 1992. 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