The bacterial fatty acid pathway is essential for membrane synthesis and a range of other metabolic and cellular functions. The β-ketoacyl-ACP synthases carry out the initial elongation reaction of this pathway, utilizing acetyl-CoA as a primer to elongate malonyl-ACP by two carbons, and subsequent elongation of the fatty acyl-ACP substrate by two carbons. Here we describe the structures of the β-ketoacyl-ACP synthase I from Brucella melitensis in complex with platencin, 7-hydroxycoumarin, and (5-thiophen-2-ylisoxazol-3-yl)methanol. The enzyme is a dimer and based on structural and sequence conservation, harbors the same active site configuration as other β-ketoacyl-ACP synthases. The platencin binding site overlaps with the fatty acyl compound supplied by ACP, while 7-hydroxyl-coumarin and (5-thiophen-2-ylisoxazol-3-yl)methanol bind at the secondary fatty acyl binding site. These high-resolution structures, ranging between 1.25 and 1.70 å resolution, provide a basis for in silico inhibitor screening and optimization, and can aid in rational drug design by revealing the high-resolution binding interfaces of molecules at the malonyl-ACP and acyl-ACP active sites.

中文翻译：

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β-酮脂酰 ACP 合酶 I 在两个底物结合位点与平板蛋白和片段筛选分子结合的结构表征。

细菌脂肪酸途径对于膜合成以及一系列其他代谢和细胞功能至关重要。β-酮酰基-ACP合酶进行该途径的初始延伸反应，利用乙酰辅酶A作为引物将丙二酰-ACP延长两个碳，然后将脂肪酰基-ACP底物延长两个碳。在这里，我们描述了来自布鲁氏菌的 β-酮酰基-ACP 合酶 I 与平板霉素、7-羟基香豆素和 (5-thiophen-2-yisoxazol-3-yl) 甲醇复合的结构。该酶是二聚体，基于结构和序列保守性，具有与其他 β-酮脂酰-ACP 合酶相同的活性位点配置。平板蛋白结合位点与 ACP 提供的脂肪酰基化合物重叠，而 7-羟基香豆素和 (5-thiophen-2-yisoxazol-3-yl)methanol 在二级脂肪酰基结合位点结合。这些高分辨率结构，分辨率介于 1.25 和 1.70 之间，为计算机抑制剂筛选和优化提供了基础，并且可以通过揭示丙二酰-ACP 和酰基-分子的高分辨率结合界面来帮助合理的药物设计。 ACP 活动站点。