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Title
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Structural basis for the exceptional in vivo efficacy of bisphosphonate drugs.
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Authors
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J.M.Rondeau,
F.Bitsch,
E.Bourgier,
M.Geiser,
R.Hemmig,
M.Kroemer,
S.Lehmann,
P.Ramage,
S.Rieffel,
A.Strauss,
J.R.Green,
W.Jahnke.
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Ref.
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Chemmedchem, 2006,
1,
267-273.
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PubMed id
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Abstract
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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.
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