1YV5

Human farnesyl diphosphate synthase complexed with Mg and risedronate

Summary for 1YV5

• Entry DOI: 10.2210/pdb1yv5/pdb
• Related: 1YQ7
• Descriptor: Farnesyl pyrophosphate synthetase, MAGNESIUM ION, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: isoprenoid pathway, cholesterol synthesis, bisphosphonate, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 43559.75

Authors

Kavanagh, K.L.,Guo, K.,Von Delft, F.,Arrowsmith, C.,Sundstrom, M.,Edwards, A.,Oppermann, U.,Structural Genomics Consortium (SGC) (deposition date: 2005-02-15, release date: 2005-03-01, Last modification date: 2023-10-25)

Primary citation

Kavanagh, K.L.,Guo, K.,Dunford, J.E.,Wu, X.,Knapp, S.,Ebetino, F.H.,Rogers, M.J.,Russell, R.G.,Oppermann, U.
The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.
Proc.Natl.Acad.Sci.USA, 103:7829-7834, 2006

PubMed Abstract: Osteoporosis and low bone mass are currently estimated to be a major public health risk affecting >50% of the female population over the age of 50. Because of their bone-selective pharmacokinetics, nitrogen-containing bisphosphonates (N-BPs), currently used as clinical inhibitors of bone-resorption diseases, target osteoclast farnesyl pyrophosphate synthase (FPPS) and inhibit protein prenylation. FPPS, a key branchpoint of the mevalonate pathway, catalyzes the successive condensation of isopentenyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. To understand the molecular events involved in inhibition of FPPS by N-BPs, we used protein crystallography, enzyme kinetics, and isothermal titration calorimetry. We report here high-resolution x-ray structures of the human enzyme in complexes with risedronate and zoledronate, two of the leading N-BPs in clinical use. These agents bind to the dimethylallyl/geranyl pyrophosphate ligand pocket and induce a conformational change. The interactions of the N-BP cyclic nitrogen with Thr-201 and Lys-200 suggest that these inhibitors achieve potency by positioning their nitrogen in the proposed carbocation-binding site. Kinetic analyses reveal that inhibition is competitive with geranyl pyrophosphate and is of a slow, tight binding character, indicating that isomerization of an initial enzyme-inhibitor complex occurs with inhibitor binding. Isothermal titration calorimetry indicates that binding of N-BPs to the apoenzyme is entropy-driven, presumably through desolvation entropy effects. These experiments reveal the molecular binding characteristics of an important pharmacological target and provide a route for further optimization of these important drugs.

PubMed: 16684881
DOI: 10.1073/pnas.0601643103

Experimental method

X-RAY DIFFRACTION (2 Å)