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1yv5
From Proteopedia
| 1yv5, resolution 2.00Å () | |||||||||
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| Sites: | , , , , and | ||||||||
| Ligands: | , , | ||||||||
| Gene: | FDPS (Homo sapiens) | ||||||||
| Activity: | Geranyltranstransferase, with EC number 2.5.1.10 | ||||||||
| Related: | 1yq7 | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Human farnesyl diphosphate synthase complexed with Mg and risedronate
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.
The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs., Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U, Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34. Epub 2006 May 9. PMID:16684881
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
1YV5 is a 1 chain structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7829-34. Epub 2006 May 9. PMID:16684881
Page seeded by OCA on Wed Jan 13 13:06:02 2010
Categories: Geranyltranstransferase | Homo sapiens | Arrowsmith, C. | Delft, F Von. | Edwards, A. | Guo, K. | Kavanagh, K L. | Oppermann, U. | SGC, Structural Genomics Consortium. | Sundstrom, M. | Bisphosphonate | Cholesterol synthesis | Isoprenoid pathway | Sgc | Structural genomic | Structural genomics consortium | Transferase
