2f8c

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Revision as of 19:54, 12 November 2007

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spinqualitylabelsall models 2f8c, resolution 2.200Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of FPPS in complex with Zoledronate

Overview

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

2F8C is a Single protein structure of sequence from Homo sapiens with PO4, MG and ZOL as ligands. Full crystallographic information is available from OCA.

Reference

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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