4L2X

Crystal structure of human FPPS in complex with magnesium, CL02134, and inorganic pyrophosphate

Summary for 4L2X

• Entry DOI: 10.2210/pdb4l2x/pdb
• Related: 4JVJ
• Descriptor: Farnesyl pyrophosphate synthase, ({[6-(4-cyclopropylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methanediyl)bis(phosphonic acid), PYROPHOSPHATE 2-, ... (5 entities in total)
• Functional Keywords: 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: 43835.19

Authors

Park, J.,Leung, C.-Y.,Tsantrizos, Y.S.,Berghuis, A.M. (deposition date: 2013-06-04, release date: 2014-01-01, Last modification date: 2023-09-20)

Primary citation

Leung, C.Y.,Park, J.,De Schutter, J.W.,Sebag, M.,Berghuis, A.M.,Tsantrizos, Y.S.
Thienopyrimidine Bisphosphonate (ThPBP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase: Optimization and Characterization of the Mode of Inhibition.
J.Med.Chem., 56:7939-7950, 2013

PubMed Abstract: Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.

PubMed: 23998921
DOI: 10.1021/jm400946f

Experimental method

X-RAY DIFFRACTION (2.55 Å)