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1x8t
From Proteopedia
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| , resolution 1.9Å | |||||||
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| Ligands: | , | ||||||
| Gene: | aroA (Escherichia coli) | ||||||
| Activity: | 3-phosphoshikimate 1-carboxyvinyltransferase, with EC number 2.5.1.19 | ||||||
| Related: | 1X8R, 1G6S, 1G6T, 1MI4, 1Q36
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
EPSPS liganded with the (R)-phosphonate analog of the tetrahedral reaction intermediate
Overview
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.
About this Structure
1X8T 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 Mar 31 00:46:14 2008
