Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
Guo
Rey-Ting
RT
Taiwan International Graduate Program, Institute of Biological Chemistry, Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan.
Cao
Rong
R
Liang
Po-Huang
PH
Ko
Tzu-Ping
TP
Chang
Tao-Hsin
TH
Hudock
Michael P
MP
Jeng
Wen-Yih
WY
Chen
Cammy K-M
CK
Zhang
Yonghui
Y
Song
Yongcheng
Y
Kuo
Chih-Jung
CJ
Yin
Fenglin
F
Oldfield
Eric
E
Wang
Andrew H-J
AH
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D011756:Diphosphates / Q000737:chemistry / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry* / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity; D014166:Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
D011756:Diphosphates; D004164:Diphosphonates; D004224:Diterpenes; D007527:Isoenzymes; D008024:Ligands; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; C511282:geranyl diphosphate; C004808:farnesyl pyrophosphate; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C106821:cis-prenyl transferase; D051231:Farnesyltranstransferase; C023266:undecaprenyl pyrophosphate synthetase; C002963:geranylgeranyl pyrophosphate