Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis

被引:228
作者
Hosfield, DJ
Zhang, YM
Dougan, DR
Broun, A
Tari, LW
Swanson, RV
Finn, J
机构
[1] Syrrx Inc, Dept Struct Chem, San Diego, CA 92121 USA
[2] Tril Pharmaceut, San Diego, CA 92121 USA
关键词
D O I
10.1074/jbc.C300511200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl pyrophosphate through successive condensations of isopentyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. Nitrogen-containing bisphosphonate drugs used to treat osteoclast-mediated bone resorption and tumor-induced hypercalcemia are potent inhibitors of the enzyme. Here we present crystal structures of substrate and bisphosphonate complexes of FPPS. The structures reveal how enzyme conformational changes organize conserved active site residues to exploit metal-induced ionization and substrate positioning for catalysis. The structures further demonstrate how nitrogen-containing bisphosphonates mimic a carbocation intermediate to inhibit the enzyme. Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer.
引用
收藏
页码:8526 / 8529
页数:4
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