5JV1
Crystal structure of human FPPS in complex with an allosteric inhibitor CL-08-066
Summary for 5JV1
| Entry DOI | 10.2210/pdb5jv1/pdb |
| Related | 5JUZ 5JV0 5JV2 |
| Descriptor | Farnesyl pyrophosphate synthase, SULFATE ION, [(1R)-1-{[6-(3-chloro-4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}-2-(3-fluorophenyl)ethyl]phosphonic acid, ... (4 entities in total) |
| Functional Keywords | 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 | 44292.86 |
| Authors | Park, J.,Leung, C.Y.,Tsantrizos, Y.S.,Berghuis, A.M. (deposition date: 2016-05-10, release date: 2017-03-15, Last modification date: 2023-09-27) |
| Primary citation | Park, J.,Leung, C.Y.,Matralis, A.N.,Lacbay, C.M.,Tsakos, M.,Fernandez De Troconiz, G.,Berghuis, A.M.,Tsantrizos, Y.S. Pharmacophore Mapping of Thienopyrimidine-Based Monophosphonate (ThP-MP) Inhibitors of the Human Farnesyl Pyrophosphate Synthase. J. Med. Chem., 60:2119-2134, 2017 Cited by PubMed Abstract: The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition. PubMed: 28208018DOI: 10.1021/acs.jmedchem.6b01888 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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