2f94: Difference between revisions
New page: left|200px<br /> <applet load="2f94" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f94, resolution 1.940Å" /> '''Crystal structure ... |
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[[Image:2f94.gif|left|200px]]<br /> | [[Image:2f94.gif|left|200px]]<br /><applet load="2f94" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2f94, resolution 1.940Å" /> | caption="2f94, resolution 1.940Å" /> | ||
'''Crystal structure of human FPPS in complex with ibandronate'''<br /> | '''Crystal structure of human FPPS in complex with ibandronate'''<br /> | ||
==Overview== | ==Overview== | ||
To understand the structural basis for bisphosphonate therapy of bone | To understand the structural basis for bisphosphonate therapy of bone diseases, we solved the crystal structures of human farnesyl pyrophosphate synthase (FPPS) in its unliganded state, in complex with the nitrogen-containing bisphosphonate (N-BP) drugs zoledronate, pamidronate, alendronate, and ibandronate, and in the ternary complex with zoledronate and the substrate isopentenyl pyrophosphate (IPP). By revealing three structural snapshots of the enzyme catalytic cycle, each associated with a distinct conformational state, and details about the interactions with N-BPs, these structures provide a novel understanding of the mechanism of FPPS catalysis and inhibition. In particular, the accumulating substrate, IPP, was found to bind to and stabilize the FPPS-N-BP complexes rather than to compete with and displace the N-BP inhibitor. Stabilization of the FPPS-N-BP complex through IPP binding is supported by differential scanning calorimetry analyses of a set of representative N-BPs. Among other factors such as high binding affinity for bone mineral, this particular mode of FPPS inhibition contributes to the exceptional in vivo efficacy of N-BP drugs. Moreover, our data form the basis for structure-guided design of optimized N-BPs with improved pharmacological properties. | ||
==About this Structure== | ==About this Structure== | ||
2F94 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, PO4 and BFQ as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2F94 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=PO4:'>PO4</scene> and <scene name='pdbligand=BFQ:'>BFQ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F94 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Bourgier, E.]] | [[Category: Bourgier, E.]] | ||
[[Category: Geiser, M.]] | [[Category: Geiser, M.]] | ||
[[Category: Green, J | [[Category: Green, J R.]] | ||
[[Category: Hemmig, R.]] | [[Category: Hemmig, R.]] | ||
[[Category: Jahnke, W.]] | [[Category: Jahnke, W.]] | ||
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[[Category: Ramage, P.]] | [[Category: Ramage, P.]] | ||
[[Category: Rieffel, S.]] | [[Category: Rieffel, S.]] | ||
[[Category: Rondeau, J | [[Category: Rondeau, J M.]] | ||
[[Category: Strauss, A.]] | [[Category: Strauss, A.]] | ||
[[Category: BFQ]] | [[Category: BFQ]] | ||
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[[Category: mevalonate pathway; isoprene biosynthesis; cholesterol biosynthesis; bisphosphonate inhibitor]] | [[Category: mevalonate pathway; isoprene biosynthesis; cholesterol biosynthesis; bisphosphonate inhibitor]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:18:57 2008'' | ||
Revision as of 18:18, 21 February 2008
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Crystal structure of human FPPS in complex with ibandronate
OverviewOverview
To understand the structural basis for bisphosphonate therapy of bone diseases, we solved the crystal structures of human farnesyl pyrophosphate synthase (FPPS) in its unliganded state, in complex with the nitrogen-containing bisphosphonate (N-BP) drugs zoledronate, pamidronate, alendronate, and ibandronate, and in the ternary complex with zoledronate and the substrate isopentenyl pyrophosphate (IPP). By revealing three structural snapshots of the enzyme catalytic cycle, each associated with a distinct conformational state, and details about the interactions with N-BPs, these structures provide a novel understanding of the mechanism of FPPS catalysis and inhibition. In particular, the accumulating substrate, IPP, was found to bind to and stabilize the FPPS-N-BP complexes rather than to compete with and displace the N-BP inhibitor. Stabilization of the FPPS-N-BP complex through IPP binding is supported by differential scanning calorimetry analyses of a set of representative N-BPs. Among other factors such as high binding affinity for bone mineral, this particular mode of FPPS inhibition contributes to the exceptional in vivo efficacy of N-BP drugs. Moreover, our data form the basis for structure-guided design of optimized N-BPs with improved pharmacological properties.
About this StructureAbout this Structure
2F94 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs., Rondeau JM, Bitsch F, Bourgier E, Geiser M, Hemmig R, Kroemer M, Lehmann S, Ramage P, Rieffel S, Strauss A, Green JR, Jahnke W, ChemMedChem. 2006 Feb;1(2):267-73. PMID:16892359
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