3N1W

Human FPPS COMPLEX WITH FBS_02

Summary for 3N1W

• Entry DOI: 10.2210/pdb3n1w/pdb
• Related: 3N1V 3N3L 3N45 3N46 3N49 3N5H 3N5J 3N6K
• Descriptor: FARNESYL PYROPHOSPHATE SYNTHASE, (5-chloro-1-benzothiophen-3-yl)acetic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: bisphosphonate; fragment-based screening; transferase; isoprene biosynthesis; cholesterol biosynthesis, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 40505.50

Authors

Rondeau, J.-M. (deposition date: 2010-05-17, release date: 2010-08-18, Last modification date: 2024-02-21)

Primary citation

Jahnke, W.,Rondeau, J.M.,Cotesta, S.,Marzinzik, A.,Pelle, X.,Geiser, M.,Strauss, A.,Gotte, M.,Bitsch, F.,Hemmig, R.,Henry, C.,Lehmann, S.,Glickman, J.F.,Roddy, T.P.,Stout, S.J.,Green, J.R.
Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery.
Nat.Chem.Biol., 6:660-666, 2010

PubMed Abstract: Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue.

PubMed: 20711197
DOI: 10.1038/nchembio.421

Experimental method

X-RAY DIFFRACTION (2.56 Å)