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Structural characterization of the ACDC domain from ApiAP2 proteins, a potential molecular target against apicomplexan parasites.
Acta Crystallographica Section D ( IF 2.6 ) Pub Date : 2025-01-01 , DOI: 10.1107/s2059798324012518
Marine Le Berre,Thibault Tubiana,Philippa Reuterswärd Waldner,Noureddine Lazar,Ines Li de la Sierra-Gallay,Joana M Santos,Manuel Llinás,Sylvie Nessler

The apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in Plasmodium spp. malaria parasites. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins. However, a conserved AP2-coincident domain mostly at the C-terminus (ACDC domain) is observed in a subset of the ApiAP2 proteins. The structure and function of this domain remain unknown. We report two crystal structures of ACDC domains derived from distinct Plasmodium ApiAP2 proteins, revealing a conserved, unique, noncanonical, four-helix bundle architecture. We used these structures to perform in silico docking calculations against a library of known antimalarial compounds and identified potential small-molecule ligands that bind in a highly conserved hydrophobic pocket that is present in all apicomplexan ACDC domains. These ligands provide a new molecular basis for the future design of ACDC inhibitors.

中文翻译:


来自 ApiAP2 蛋白的 ACDC 结构域的结构表征,ApiAP2 蛋白是针对顶复门寄生虫的潜在分子靶标。



顶复元 AP2 (ApiAP2) 蛋白是疟原虫属疟疾寄生虫中 DNA 结合蛋白的最佳特征家族。除了 AP2 DNA 结合结构域外,ApiAP2 蛋白之间的序列相似性很小。然而,在 ApiAP2 蛋白的子集中观察到一个主要位于 C 端(ACDC 结构域)的保守 AP2 重合结构域。该域的结构和功能仍然未知。我们报道了源自不同疟原虫 ApiAP2 蛋白的 ACDC 结构域的两种晶体结构,揭示了一种保守的、独特的、非经典的四螺旋束结构。我们使用这些结构对已知抗疟化合物库进行计算机对接计算,并确定了潜在的小分子配体,这些配体结合在所有顶复门 ACDC 结构域中存在的高度保守的疏水口袋中。这些配体为 ACDC 抑制剂的未来设计提供了新的分子基础。
更新日期:2025-01-01
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