Allostery is the process by which the binding of a ligand to a protein induces a functional response at the substrate binding site, through an alteration in structure and/or dynamics. The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyses the first committed step of the shikimate pathway, responsible for the biosynthesis of important aromatic compounds, including the amino acids; phenylalanine, tyrosine and tryptophan.¹ The flux of this pathway is controlled at the protein level via allosteric regulation. Neisseria meningitidis  DAH7PS is most potently allosterically regulated by phenylalanine.

Although no significant structural change is associated with phenylalanine binding, a comparison of the phenylalanine bound (2.2 Å) and apo (2.0 Å) crystal structures implicates several residues involved in the communication of this allosteric signal.¹  These residues comprise a hydrogen-bonding relay network which connects the remote phenylalanine binding site to the acitive site.  Molecular dynamics calculations were used to calculate pKa variations associated with phenylalanine binding.  Remarkably significant pKa variation was found most prominently associated with the proposed hydrogen bonding network. These findings illustrate the importance of the dynamic properties of N. meningitidis DAH7PS for allostery and enable the signal transduction pathway between allosteric and active sites to be delineated.

1.        P Cross, T Allison, S Wilson-Coutts, F Cochrane, A Pietersma, and E. J. Parker. Neisseria meningitidis expresses a single 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase that is inhibited primarily by phenylalanine. Protein Sci. 22, 1087–1099 (2013).