2F8Z

Crystal structure of human FPPS in complex with zoledronate and isopentenyl diphosphate

2F8Z の概要

• エントリーDOI: 10.2210/pdb2f8z/pdb
• 関連するPDBエントリー: 2F7M 2F89 2F8C 2F92 2F94 2F9K
• 分子名称: Farnesyl Diphosphate Synthase, MAGNESIUM ION, 3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: mevalonate pathway; isoprene biosynthesis; cholesterol biosynthesis; bisphosphonate inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14324
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40774.95

構造登録者

Rondeau, J.-M.,Bitsch, F.,Bourgier, E.,Geiser, M.,Hemmig, R.,Kroemer, M.,Lehmann, S.,Ramage, P.,Rieffel, S.,Strauss, A.,Green, J.R.,Jahnke, W. (登録日: 2005-12-02, 公開日: 2006-02-28, 最終更新日: 2023-08-30)

主引用文献

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

PubMed Abstract: 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.

PubMed: 16892359
DOI: 10.1002/cmdc.200500059

実験手法

X-RAY DIFFRACTION (2.6 Å)