1RQJ

Active Conformation of Farnesyl Pyrophosphate Synthase Bound to Isopentyl Pyrophosphate and Risedronate

Summary for 1RQJ

• Entry DOI: 10.2210/pdb1rqj/pdb
• Related: 1RQI 1RTR
• Descriptor: Geranyltranstransferase, MAGNESIUM ION, 3-METHYLBUT-3-ENYL TRIHYDROGEN DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: bisphosphonate, isoprenyl synthase, transferase
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P22939
• Total number of polymer chains: 2
• Total formula weight: 65599.47

Authors

Hosfield, D.J.,Zhang, Y.,Dougan, D.R.,Brooun, A.,Tari, L.W.,Swanson, R.V.,Finn, J. (deposition date: 2003-12-05, release date: 2004-03-02, Last modification date: 2024-02-14)

Primary citation

Hosfield, D.J.,Zhang, Y.,Dougan, D.R.,Brooun, A.,Tari, L.W.,Swanson, R.V.,Finn, J.
Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis
J.Biol.Chem., 279:8526-8529, 2004

PubMed Abstract: Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl pyrophosphate through successive condensations of isopentyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. Nitrogen-containing bisphosphonate drugs used to treat osteoclast-mediated bone resorption and tumor-induced hypercalcemia are potent inhibitors of the enzyme. Here we present crystal structures of substrate and bisphosphonate complexes of FPPS. The structures reveal how enzyme conformational changes organize conserved active site residues to exploit metal-induced ionization and substrate positioning for catalysis. The structures further demonstrate how nitrogen-containing bisphosphonates mimic a carbocation intermediate to inhibit the enzyme. Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer.

PubMed: 14672944
DOI: 10.1074/jbc.C300511200

Experimental method

X-RAY DIFFRACTION (1.95 Å)