4DEM

Crystal structure of human FPPS in complex with YS_04_70

Summary for 4DEM

• Entry DOI: 10.2210/pdb4dem/pdb
• Descriptor: Farnesyl pyrophosphate synthase, [({4-[4-(propan-2-yloxy)phenyl]pyridin-2-yl}amino)methanediyl]bis(phosphonic acid), MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: mevalonate pathway, isoprene biosynthesis, cholesterol biosynthesis, bisphosphonate, 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: 43620.17

Authors

Park, J.,Lin, Y.-S.,Tsantrizos, Y.S.,Berghuis, A.M. (deposition date: 2012-01-20, release date: 2012-03-21, Last modification date: 2023-09-13)

Primary citation

Lin, Y.S.,Park, J.,De Schutter, J.W.,Huang, X.F.,Berghuis, A.M.,Sebag, M.,Tsantrizos, Y.S.
Design and Synthesis of Active Site Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Apoptosis and Inhibition of ERK Phosphorylation in Multiple Myeloma Cells.
J.Med.Chem., 55:3201-3215, 2012

PubMed Abstract: Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.

PubMed: 22390415
DOI: 10.1021/jm201657x

Experimental method

X-RAY DIFFRACTION (1.85 Å)