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Two synthetic tail analogues of aplyronine\u2005C (SF\u201001 and GC\u201004) are shown to bind to G\u2010actin with dissociation constants of (285\u00b133) and (132\u00b113)\u2005n<jats:sc>M<\/jats:sc>, respectively. The crystal structures of actin complexes with GC\u201004, SF\u201001, and kabiramide\u2005C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1\/SD3 cleft on the upper protomer, which displaces loop\u2010D from the lower protomer on the same half\u2010filament. With previous studies showing that the GC\u201004 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F\u2010actin would make them more effective at severing filaments compared with plasma gelsolin. Structure\u2010based analyses are used to suggest more reactive or targetable forms of GC\u201004 and SF\u201001, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.<\/jats:p>","DOI":"10.1002\/cmdc.201402150","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T05:53:38Z","timestamp":1406008418000},"page":"2286-2293","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues"],"prefix":"10.1002","volume":"9","author":[{"given":"Jose H.","family":"Pereira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chutima","family":"Petchprayoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander C.","family":"Hoepker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel W.","family":"Moriarty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Fink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cecere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Paterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Marriott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,7,22]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00120-X"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0171-9335(98)80075-7"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.5.1035"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.3.9.1015"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90036-5"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1006"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2233339100"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026033452348"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)01206-6"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502089102"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)85019-5"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2008.07.132"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2008.01.010"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199908000-00002"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-06-1672"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.2310\/6650.2002.33518"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200290059"},{"key":"e_1_2_6_17_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200290057"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/asia.200700357"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol401327r"},{"key":"e_1_2_6_20_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1182\/blood.V72.1.214.214","volume":"72","author":"Smith D. 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