3DYF

T. Brucei Farnesyl Diphosphate Synthase Complexed with Bisphosphonate BPH-461 and Isopentyl Diphosphate

Summary for 3DYF

• Entry DOI: 10.2210/pdb3dyf/pdb
• Related: 2EWG 2I19 2OGD 3DYG 3DYH
• Descriptor: FARNESYL PYROPHOSPHATE SYNTHASE, MAGNESIUM ION, ACETATE ION, ... (8 entities in total)
• Functional Keywords: protein-bisphosphonate complex, isoprene biosynthesis, transferase
• Biological source: Trypanosoma brucei
• Total number of polymer chains: 2
• Total formula weight: 90453.09

Authors

Cao, R.,Gao, Y.,Robinson, H.,Goddard, A.,Oldfield, E. (deposition date: 2008-07-27, release date: 2009-05-05, Last modification date: 2024-02-21)

Primary citation

Zhang, Y.,Cao, R.,Yin, F.,Hudock, M.P.,Guo, R.T.,Krysiak, K.,Mukherjee, S.,Gao, Y.G.,Robinson, H.,Song, Y.,No, J.H.,Bergan, K.,Leon, A.,Cass, L.,Goddard, A.,Chang, T.K.,Lin, F.Y.,Van Beek, E.,Papapoulos, S.,Wang, A.H.,Kubo, T.,Ochi, M.,Mukkamala, D.,Oldfield, E.
Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
J.Am.Chem.Soc., 131:5153-5162, 2009

PubMed Abstract: Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

PubMed: 19309137
DOI: 10.1021/ja808285e

Experimental method

X-RAY DIFFRACTION (2.65 Å)