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Review
. 2001 Mar 13;98(6):2944-6.
doi: 10.1073/pnas.061025898.

Closing down on glyphosate inhibition--with a new structure for drug discovery

M F Alibhai  1 , W C Stallings
Affiliations
Review

Closing down on glyphosate inhibition--with a new structure for drug discovery

M F Alibhai et al. Proc Natl Acad Sci U S A. .
No abstract available

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Figures

Scheme 1
Scheme 1
Figure 1
Figure 1
Folding and topological symmetry of EPSPS (adapted from ref. 11). The two domain structure is formed by 6-fold replication of a protein folding unit (Upper) comprising two parallel helices and a four-stranded β-sheet. Each domain is formed from three of these folding units, which are related by an approximate 3-fold topological symmetry axis. In the open form of EPSPS, these axes are not collinear, but are presumably more so in the closed formed of the enzyme reported by Schönbrunn et al. (10). In each domain, three of the helices are buried and the surface of the molecule formed from the three β-sheets and the solvent-accessible faces of the other three helices. The N and C termini are located in Domain 1 with two crossover polypeptide segments creating a double hinge that links the two domains (Lower). Among the six folding units, three are folded from continuous segments of polypeptide chain. The other three contain the same arrangement of secondary structural features, but the sequences are not from a continuous chain. The arrangement positions the N termini of all 12 helices near the interface that results when the enzyme closes to form the active site. The positive macrodipoles from these helices presumably contribute to binding of substrates, products, and inhibitors, which are all multiply charged anions.
Figure 2
Figure 2
(Left) Space-filling model of E. coli EPSPS in the open form. (Right) Model of an EPSPS molecule in the closed, ligand-bound form. Comparisons of the figures illustrate the dramatic conformational change that attends ligand binding.
Figure 3
Figure 3
Crystal structure of the open form of EPSPS. Schönbrunn et al. (10) identify residues in MurA and their homologs in EPSPS that are determinants in the control of domain closure, and suggest that inhibitors that bind to these residues will interfere with closure of the enzymes and the formation of their active sites. Arg-100 (Upper, or Domain 2) is relatively close to the active site. Asp-384 is in the Lower domain (Domain 1). Asp-242 is near the two-stranded hinge that links the two domains.
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