2F9K

Crystal structure of human FPPS in complex with Zoledronate and Zn2+

Summary for 2F9K

• Entry DOI: 10.2210/pdb2f9k/pdb
• Related: 2F7M 2F89 2F8C 2F8Z 2F92 2F94
• Descriptor: Farnesyl Diphosphate Synthase, ZINC ION, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: mevalonate pathway; isoprene biosynthesis; cholesterol biosynthesis; bisphosphonate inhibitor, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 40747.14

Authors

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. (deposition date: 2005-12-06, release date: 2006-02-28, Last modification date: 2024-02-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.06 Å)