1rtr
From Proteopedia
(New page: 200px<br /><applet load="1rtr" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rtr, resolution 2.50Å" /> '''Crystal Structure of...) |
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| - | [[Image:1rtr.jpg|left|200px]]<br /><applet load="1rtr" size=" | + | [[Image:1rtr.jpg|left|200px]]<br /><applet load="1rtr" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1rtr, resolution 2.50Å" /> | caption="1rtr, resolution 2.50Å" /> | ||
'''Crystal Structure of S. Aureus Farnesyl Pyrophosphate Synthase'''<br /> | '''Crystal Structure of S. Aureus Farnesyl Pyrophosphate Synthase'''<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== | ||
| - | 1RTR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http:// | + | 1RTR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RTR OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Staphylococcus aureus]] | [[Category: Staphylococcus aureus]] | ||
[[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: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:54:31 2008'' |
Revision as of 12:54, 21 February 2008
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Crystal Structure of S. Aureus Farnesyl Pyrophosphate Synthase
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
1RTR is a Single protein structure of sequence from Staphylococcus aureus. 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
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