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首页> 外文期刊>Acta crystallographica. Section D, Biological crystallography. >Structural characterization of substrate and inhibitor binding to farnesyl pyrophosphate synthase from Pseudomonas aeruginosa
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Structural characterization of substrate and inhibitor binding to farnesyl pyrophosphate synthase from Pseudomonas aeruginosa

机译：底物的结构特征焦磷酸通过抑制剂具有约束力合酶从铜绿假单胞菌

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摘要

Locus PA4043 in the genome of Pseudomonas aeruginosa PAO1 has been annotated as coding for a farnesyl pyrophosphate synthase (FPPS). This open reading frame was cloned and expressed recombinantly in Escherichia coli. The dimeric enzyme shows farnesyl pyrophosphate synthase activity and is strongly inhibited by ibandronate and zoledronate, drugs that are presently in clinical use. The structures of the unliganded enzyme and complexes with the substrate geranyl diphosphate (GPP), the inhibitor ibandronate and two compounds obtained from a differential scanning fluorimetry-based screen of a fragment library were determined by X-ray crystallography to resolutions of better than 2.0 angstrom. The enzyme shows the typical alpha-helical fold of farnesyl pyrophosphate synthases. The substrate GPP binds in the S1 substrate site in an open conformation of the enzyme. In the enzyme-ibandronate complex three inhibitor molecules are bound in the active site of the enzyme. One inhibitor molecule occupies the allylic substrate site (S1) of each subunit, as observed in complexes of nitrogen-containing bisphosphonate inhibitors of farnesyl synthases from other species. Two (in subunit A) and one (in subunit B) additional ibandronate molecules are bound in the active site. The structures of the fragment complexes show two molecules bound in a hydrophobic pocket adjacent to the active site. This allosteric pocket, which has previously only been described for FPPS from eukaryotic organisms, is thus also present in enzymes from pathogenic prokaryotes and might be utilized for the design of inhibitors of bacterial FPPS with a different chemical scaffold to the highly charged bisphosphonates, which are less likely to pass bacterial membranes.
机译：轨迹PA4043假单胞菌的基因组绿脓杆菌PAO1被注解为编码通过焦磷酸合成酶(FPPS)。开放阅读框是克隆和表达重组大肠杆菌。酶显示通过焦磷酸合酶活动和由ibandronate强烈抑制和zoledronate,目前药物临床使用。酶与底物复合物香叶二磷酸(GPP)抑制剂ibandronate和从微分获得的两种化合物扫描fluorimetry-based屏幕的一个片段图书馆是由x射线晶体学比2.0埃分辨率。酶显示了典型的α螺旋折叠通过焦磷酸合成酶。GPP结合S1衬底的网站在一个开放的酶的构象。enzyme-ibandronate复杂三抑制剂分子的活性部位酶。每个亚基的烯丙基的衬底网站(S1),观察到氮含量的复合物二磷酸盐通过合成酶的抑制剂从其他物种。(B亚基)额外ibandronate分子注定在活动网站。片段复合物显示两个分子结合在疏水口袋附近活动网站。以前只对FPPS从被描述真核生物,因此也出现在酶从致病原核生物和可能利用抑制剂的设计细菌FPPS具有不同化学脚手架在高度紧张,不太可能通过细菌膜。

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