Download MendeleyThe molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.
Kavanagh, K.L., Guo, K., Dunford, J.E., Wu, X., Knapp, S., Ebetino, F.H., Rogers, M.J., Russell, R.G., Oppermann, U.(2006) Proc Natl Acad Sci U S A 103: 7829-7834
- PubMed: 16684881
- DOI: https://doi.org/10.1073/pnas.0601643103
- Primary Citation of Related Structures:
1YV5, 1ZW5 - 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.
Organizational Affiliation:
Structural Genomics Consortium, University of Oxford, Oxford OX3 7LD, United Kingdom. [email protected]
