Structural and biochemical studies of actin in complex with synthetic macrolide tail analogues.
Structural and biochemical studies of actin in complex with synthetic macrolide tail analogues.
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DOI：
10.1002/cmdc.201402150
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发表时间：
2014-10
期刊：
影响因子：
3.4
通讯作者：
Marriott, Gerard
中科院分区：
文献类型：
--
作者：
Pereira, Jose H.;Petchprayoon, Chutima;Hoepker, Alexander C.;Moriarty, Nigel W.;Fink, Sarah J.;Cecere, Giuseppe;Paterson, Ian;Adams, Paul D.;Marriott, Gerard
海洋大环内酯类的阿托洛宁、卡比胺和瑞地潘基文家族的肌动蛋白免疫结合和免疫切断活性位于分子的疏水尾部区域内。两种合成的阿克罗宁C尾部类似物（SF-01和GC-04）与G-肌动蛋白结合的kd值分别为285 +/-33 nM和132 +/-13 nM。肌动蛋白复合物与GC-04，SF-01和kabiramide C的晶体结构揭示了一个保守的模式，在子结构域（SD）1和3之间形成的裂缝内的尾部结合。我们的研究支持这样的观点，即丝切断是由尾部区域特异性结合到上原聚体上的SD 1/3裂缝引起的，该裂缝在相同的半丝上从下原聚体置换环D。先前的研究表明GC-04类似物可以切断肌动蛋白丝，有人认为，与血浆凝溶胶蛋白相比，尾部类似物与F-肌动蛋白的较短复合物寿命将使它们在切断细丝方面更有效。基于结构的分析被用于提示GC-04和SF-01的更具反应性或靶向性的形式，这可能有助于提高血清肌动蛋白清除系统的能力，产生针对肿瘤细胞抗原的抗体缀合物，并降低囊性纤维化儿童的痰液粘度。
The actin filament-binding and filament-severing activities of the aplyronine, kabiramide and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogs of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with kd values of 285 +/−33 nM and 132 +/−13 nM, respectively. The crystal structures of actin complexes with GC-04, SF-01 and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between sub-domains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that GC-04 analog can sever actin filaments, it is argued that the shorter complex lifetime of tail analogs with F-actin would make them more effective at severing filaments compared with plasma gelsolin. Structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to reduce sputum viscosity in children with cystic fibrosis.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.1
作者：
Dahl, B;Schiodt, FV;Lee, WM
通讯作者：
Lee, WM
影响因子：
16.6
作者：
Hagelueken, Gregor;Albrecht, Simone C.;Schubert, Wolf-Dieter
通讯作者：
Schubert, Wolf-Dieter
影响因子：
--
作者：
Klenchin, VA;King, R;Rayment, I
通讯作者：
Rayment, I
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH