4JVJ
Crystal structure of human FPPS in complex with magnesium, CL01131, and sulfate
Summary for 4JVJ
| Entry DOI | 10.2210/pdb4jvj/pdb |
| Related | 4L2X |
| Descriptor | Farnesyl pyrophosphate synthase, ({[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methanediyl)bis(phosphonic acid), SULFATE ION, ... (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 | 43729.26 |
| Authors | Park, J.,Leung, C.-Y.,Tsantrizos, Y.S.,Berghuis, A.M. (deposition date: 2013-03-25, 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 Cited by 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: 23998921DOI: 10.1021/jm400946f PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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