APOBEC3s (A3) are Zn(2+) dependent cytidine deaminases with diverse biological functions and implications for cancer and immunity. Four of the seven human A3s restrict HIV by 'hypermutating' the reverse-transcribed viral genomic DNA. HIV Virion Infectivity Factor (Vif) counters this restriction by targeting A3s to proteasomal degradation. However, there is no apparent correlation between catalytic activity, Vif binding, and sequence similarity between A3 domains. Our comparative structural analysis reveals features required for binding Vif and features influencing polynucleotide deaminase activity in A3 proteins. All Vif-binding A3s share a negatively charged surface region that includes residues previously implicated in binding the highly-positively charged Vif. Additionally, catalytically active A3s share a positively charged groove near the Zn(2+) coordinating active site, which may accommodate the negatively charged polynucleotide substrate. Our findings suggest surface electrostatics, as well as the spatial extent of substrate accommodating region, are critical determinants of substrate and Vif binding across A3 proteins with implications for anti-retroviral and anti-cancer therapeutic design.

中文翻译：

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对APOBEC3催化活性和对HIV-1 Vif的脆弱性的结构决定因素的计算分析。

APOBEC3s（A3）是依赖Zn（2+）的胞苷脱氨酶，具有多种生物学功能以及对癌症和免疫力的影响。七个人类A3中的四个通过“超突变”逆转录病毒基因组DNA来限制HIV。HIV病毒感染因子（Vif）通过将A3靶向蛋白酶体降解来克服这种限制。但是，催化活性，Vif结合和A3域之间的序列相似性之间没有明显的相关性。我们的比较结构分析揭示了结合Vif所需的功能以及影响A3蛋白中多核苷酸脱氨酶活性的功能。所有与Vif结合的A3共有一个带负电荷的表面区域，该区域包括先前与结合带正电的Vif有关的残基。另外，具有催化活性的A3s在Zn（2+）配位活性位点附近共享带正电荷的凹槽，可容纳带负电荷的多核苷酸底物。我们的发现表明表面静电以及底物容纳区域的空间范围是跨A3蛋白的底物和Vif结合的关键决定因素，对抗逆转录病毒和抗癌治疗设计具有重要意义。