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| - | [[Image:1x8r.gif|left|200px]] | + | {{Seed}} |
| | + | [[Image:1x8r.png|left|200px]] |
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| | {{STRUCTURE_1x8r| PDB=1x8r | SCENE= }} | | {{STRUCTURE_1x8r| PDB=1x8r | SCENE= }} |
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| - | '''EPSPS liganded with the (S)-phosphonate analog of the tetrahedral reaction intermediate'''
| + | ===EPSPS liganded with the (S)-phosphonate analog of the tetrahedral reaction intermediate=== |
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| - | ==Overview==
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| - | The enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes the penultimate step of the shikimate pathway and is the target of the broad-spectrum herbicide glyphosate. Since the functionality of the shikimate pathway is vital not only for plants but also for microorganisms, EPSPS is considered a prospective target for the development of novel antibiotics. We have kinetically analyzed and determined the crystal structures of Escherichia coli EPSPS inhibited by (R)- and (S)-configured phosphonate analogues of the tetrahedral reaction intermediate. Both diastereomers are competitive inhibitors with respect to the substrates of the EPSPS reaction, shikimate-3-phosphate (S3P) and phosphoenolpyruvate (PEP). Remarkably, the (S)-phosphonate (K(iS3P) = 750 nM), whose configuration corresponds to that of the genuine tetrahedral intermediate, is a much weaker inhibitor than the (R)-phosphonate analogue (K(iS3P) = 16 nM). The crystal structures of EPSPS liganded with the (S)- and (R)-phosphonates, at 1.5 and 1.9 A resolution, respectively, revealed that binding of the (R)-phosphonate induces conformational changes of the strictly conserved residues Arg124 and Glu341 within the active site. This appears to give rise to substantial structural alterations in the amino-terminal globular domain of the enzyme. By contrast, binding of the (S)-phosphonate renders the enzyme structure unchanged. Thus, EPSPS may facilitate the tight binding of structurally diverse ligands through conformational flexibility. Molecular docking calculations did not explain why the (R)-phosphonate is the better inhibitor. Therefore, we propose that the structural events during the open-closed transition of EPSPS are altered as a result of inhibitor action. | + | The line below this paragraph, {{ABSTRACT_PUBMED_15736934}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15736934 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15736934}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Schonbrunn, E.]] | | [[Category: Schonbrunn, E.]] |
| | [[Category: Inside-out alpha-beta barrel]] | | [[Category: Inside-out alpha-beta barrel]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 14:42:48 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 15:50:31 2008'' |
Revision as of 12:50, 28 July 2008
Template:STRUCTURE 1x8r
EPSPS liganded with the (S)-phosphonate analog of the tetrahedral reaction intermediate
Template:ABSTRACT PUBMED 15736934
About this Structure
1X8R is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Interaction of phosphonate analogues of the tetrahedral reaction intermediate with 5-enolpyruvylshikimate-3-phosphate synthase in atomic detail., Priestman MA, Healy ML, Becker A, Alberg DG, Bartlett PA, Lushington GH, Schonbrunn E, Biochemistry. 2005 Mar 8;44(9):3241-8. PMID:15736934
Page seeded by OCA on Mon Jul 28 15:50:31 2008
