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The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2006 May 16; Vol. 103 (20), pp. 7829-34. Date of Electronic Publication: 2006 May 09. - Publication Year :
- 2006
-
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.
- Subjects :
- Animals
Bone Density Conservation Agents chemistry
Crystallography, X-Ray
Diphosphonates chemistry
Etidronic Acid analogs & derivatives
Etidronic Acid chemistry
Etidronic Acid therapeutic use
Female
Geranyltranstransferase antagonists & inhibitors
Geranyltranstransferase genetics
Geranyltranstransferase metabolism
Humans
Imidazoles chemistry
Imidazoles therapeutic use
Models, Molecular
Molecular Sequence Data
Molecular Structure
Nitrogen chemistry
Protein Binding
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
Risedronic Acid
Zoledronic Acid
Bone Density Conservation Agents therapeutic use
Diphosphonates metabolism
Diphosphonates therapeutic use
Geranyltranstransferase chemistry
Nitrogen metabolism
Protein Conformation
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 103
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 16684881
- Full Text :
- https://doi.org/10.1073/pnas.0601643103