1rqi
From Proteopedia
(New page: 200px<br /><applet load="1rqi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rqi, resolution 2.42Å" /> '''Active Conformation ...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1rqi.gif|left|200px]]<br /><applet load="1rqi" size=" | + | [[Image:1rqi.gif|left|200px]]<br /><applet load="1rqi" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1rqi, resolution 2.42Å" /> | caption="1rqi, resolution 2.42Å" /> | ||
'''Active Conformation of Farnesyl Pyrophosphate Synthase Bound to Isopentyl Pyrophosphate and Dimethylallyl S-Thiolodiphosphate'''<br /> | '''Active Conformation of Farnesyl Pyrophosphate Synthase Bound to Isopentyl Pyrophosphate and Dimethylallyl S-Thiolodiphosphate'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1RQI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with MG, DST, IPR and DPO as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Geranyltranstransferase Geranyltranstransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.10 2.5.1.10] Full crystallographic information is available from [http:// | + | 1RQI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=DST:'>DST</scene>, <scene name='pdbligand=IPR:'>IPR</scene> and <scene name='pdbligand=DPO:'>DPO</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Geranyltranstransferase Geranyltranstransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.10 2.5.1.10] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RQI OCA]. |
==Reference== | ==Reference== | ||
| Line 15: | Line 15: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Brooun, A.]] | [[Category: Brooun, A.]] | ||
| - | [[Category: Dougan, D | + | [[Category: Dougan, D R.]] |
[[Category: Finn, J.]] | [[Category: Finn, J.]] | ||
| - | [[Category: Hosfield, D | + | [[Category: Hosfield, D J.]] |
| - | [[Category: Swanson, R | + | [[Category: Swanson, R V.]] |
| - | [[Category: Tari, L | + | [[Category: Tari, L W.]] |
[[Category: Zhang, Y.]] | [[Category: Zhang, Y.]] | ||
[[Category: DPO]] | [[Category: DPO]] | ||
| Line 27: | Line 27: | ||
[[Category: isoprenyl synthase]] | [[Category: isoprenyl synthase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:53:34 2008'' |
Revision as of 12:53, 21 February 2008
|
Active Conformation of Farnesyl Pyrophosphate Synthase Bound to Isopentyl Pyrophosphate and Dimethylallyl S-Thiolodiphosphate
Overview
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.
About this Structure
1RQI is a Single protein structure of sequence from Escherichia coli with , , and as ligands. Active as Geranyltranstransferase, with EC number 2.5.1.10 Full crystallographic information is available from OCA.
Reference
Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis., Hosfield DJ, Zhang Y, Dougan DR, Broun A, Tari LW, Swanson RV, Finn J, J Biol Chem. 2004 Mar 5;279(10):8526-9. Epub 2003 Dec 12. PMID:14672944
Page seeded by OCA on Thu Feb 21 14:53:34 2008
Categories: Escherichia coli | Geranyltranstransferase | Single protein | Brooun, A. | Dougan, D R. | Finn, J. | Hosfield, D J. | Swanson, R V. | Tari, L W. | Zhang, Y. | DPO | DST | IPR | MG | Isoprenyl synthase
