Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases
Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases
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DOI：
10.1002/prot.22066
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发表时间：
2008-11-01
影响因子：
2.9
通讯作者：
Oldfield, Eric
中科院分区：
文献类型：
--
作者：
Cao, Rong;Chen, Cammy K. -M.;Oldfield, Eric
我们报道了与布氏锥虫的法尼基二磷酸合成酶和酿酒酵母的香叶基香叶基二磷酸合成酶结合的双膦酸类N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1，1-bisphosphonate(BPH-210)的结构。BPH-210与3个镁离子结合在一起，其长长的疏水性苯丁基侧链与烯丙基二磷酸盐和其他双磷酸盐位于同一结合口袋中。结合是由等温滴定量热法确定的，绝大多数是由熵驱动的。人们对这种结构很感兴趣，因为它解释了为什么较长的链类似物对FPPS缺乏效力，因为这些类似物预计会与结合位点末端的芳香环发生空间碰撞。与帕米磷酸钠等短链FPPS抑制剂不同，BPH-210也被发现是人类香叶基香叶基二磷酸合成酶的有效抑制剂。在这种情况下，双膦酸根只与GGPP产物的抑制部位结合，只与I(A链)或0(B链)的镁离子结合，而AS要小得多，AH类似于6kcal，比FPPS结合时更负。总体而言，这些结果是普遍感兴趣的，因为它们表明联二磷酸盐可以与不止一种反式戊烯基合酶结合，在联用情况下，有望提高它们在体外和体内的整体活性。
We report tire X-ray crystallographic structures of the bisphosphonate N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (BPH-210), a potent analog of pamidronate (Aredia), bound to farnesyl diphosphate synthase (FPPS) from Trypanosoma brucei as well as to geranylgeranyl diphosphate synthase from Saccharomyces cerevisiae. BPH-210 binds to FPPS, together with 3 Mg2+, with its long, hydrophobic phenylbutyl side-chain being located in the same binding pocket that is occupied by allylic diphosphates and other bisphosphonates. Binding is overwhelmingly entropy driven, as determined by isothermal titration calorimetty. The structure is of interest since it explains the lack of potency of longer chain analogs against FPPS, since these would be expected to have a steric clash with an aromatic ring at the distal end of the binding site. Unlike shorter chain FPPS inhibitors, such as pamidronate, BPH-210 is also found to be a potent inhibitor of human geranylgeranyl diphosphate synthase. In this case, the bisphosphonate binds only to tire GGPP product inhibitory site, with only I (chain A) or 0 (chain B) Mg2+, and AS is much smaller and AH is similar to 6 k cal more negative than in the case of FPPS binding. Overall, these results are of general interest since they show that sortie bisphosphonates can bind to more than one trans-prenyl synthase enzyme which, in sortie cases, can be expected to enhance their overall activity in vitro and in vivo.