5DJR
Crystal structure of human FPPS in complex with biaryl compound 6
Summary for 5DJR
| Entry DOI | 10.2210/pdb5djr/pdb |
| Related | 5DGN 5DIQ 5DJP |
| Descriptor | Farnesyl pyrophosphate synthase, GLYCEROL, 1H,1'H-4,4'-biindole-2-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | transferase, isoprene biosynthesis, cholesterol biosynthesis |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm: P14324 |
| Total number of polymer chains | 1 |
| Total formula weight | 40739.30 |
| Authors | Rondeau, J.M.,Bourgier, E.,Lehmann, S. (deposition date: 2015-09-02, release date: 2015-09-30, Last modification date: 2024-05-08) |
| Primary citation | Marzinzik, A.L.,Amstutz, R.,Bold, G.,Bourgier, E.,Cotesta, S.,Glickman, J.F.,Gotte, M.,Henry, C.,Lehmann, S.,Hartwieg, J.C.,Ofner, S.,Pelle, X.,Roddy, T.P.,Rondeau, J.M.,Stauffer, F.,Stout, S.J.,Widmer, A.,Zimmermann, J.,Zoller, T.,Jahnke, W. Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding. Chemmedchem, 10:1884-1891, 2015 Cited by PubMed Abstract: Farnesyl pyrophosphate synthase (FPPS) is an established target for the treatment of bone diseases, but also shows promise as an anticancer and anti-infective drug target. Currently available anti-FPPS drugs are active-site-directed bisphosphonate inhibitors, the peculiar pharmacological profile of which is inadequate for therapeutic indications beyond bone diseases. The recent discovery of an allosteric binding site has paved the way toward the development of novel non-bisphosphonate FPPS inhibitors with broader therapeutic potential, notably as immunomodulators in oncology. Herein we report the discovery, by an integrated lead finding approach, of two new chemical classes of allosteric FPPS inhibitors that belong to the salicylic acid and quinoline chemotypes. We present their synthesis, biochemical and cellular activities, structure-activity relationships, and provide X-ray structures of several representative FPPS complexes. These novel allosteric FPPS inhibitors are devoid of any affinity for bone mineral and could serve as leads to evaluate their potential in none-bone diseases. PubMed: 26381451DOI: 10.1002/cmdc.201500338 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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