2e9a: Difference between revisions

Revision as of 18:07, 21 February 2008

E. coli undecaprenyl pyrophosphate synthase in complex with BPH-628

OverviewOverview

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.

About this StructureAbout this Structure

2E9A is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Di-trans,poly-cis-decaprenylcistransferase, with EC number 2.5.1.31 Full crystallographic information is available from OCA.

ReferenceReference

Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases., Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH, Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. PMID:17535895

Page seeded by OCA on Thu Feb 21 17:07:32 2008

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OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-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 provicd de, 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.
+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.
 ==About this Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
-Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases., Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH, Proc Natl Acad Sci U S A. 2007 May 29;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17535895 17535895]
+Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases., Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH, Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17535895 17535895]
 [[Category: Di-trans,poly-cis-decaprenylcistransferase]]
 [[Category: Escherichia coli]]
 [[Category: Single protein]]
 [[Category: Cao, R.]]
-[[Category: Guo, R.T.]]
+[[Category: Guo, R T.]]
-[[Category: Ko, T.P.]]
+[[Category: Ko, T P.]]
-[[Category: Liang, P.H.]]
+[[Category: Liang, P H.]]
 [[Category: Oldfield, E.]]
-[[Category: Wang, A.H.J.]]
+[[Category: Wang, A H.J.]]
 [[Category: B28]]
 [[Category: antibiotic]]
@@ Line 27: / Line 27: @@
 [[Category: prenyltransferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:54:03 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:07:32 2008''