Finally, the Mtb DHPS structure reveals a highly conserved pterin binding pocket that may be exploited for the design of novel antimycobacterial agents.
Detailed analysis of inhibitor-Pfmrk binding interactions enabled us to identify specific residues (viz. Met66, Met75, Met91, Met94 and Phe143) within the Pfmrk binding pocket that may play an important role in inhibitor binding affinity and selectivity.
Docking studies using the antagonist TAK-779 [40] and a model of the related CCR5 receptor identified a region of the binding pocket that may act as a conserved binding point for chemokine antagonists sharing an ammonium group [41].
Furthermore, the HORMA domain of Atg13 contains a positively charged sulfate-binding pocket that may serve as a binding site for phosphate-containing molecules, such as phosphoproteins or lipids (Fig. 1A).
Alternatively, the inorganic phosphate may occupy binding pockets that are normally occupied by the phosphate moieties of NADP+ during catalysis, thereby stabilizing the enzyme.
One approach is to identify molecules that occupy the pterin binding pocket which is distinct from the pABA binding pocket that binds sulfonamides.
The HSP90 homologue gp96 also contains a binding pocket and, like HSP90, it is an open binding pocket that should allow peptides of any length to interact with it, though the presence of a disulphide bond in this domain may also affect peptide binding [ 75].
Upon inspection of the Parkin structure, we identified two further putative phospho-Ser-binding pockets that we term "Pocket 2" and "Pocket 3" (Fig 2A).
Based on a recent HLA sequencing study of FL [ 4], we showed that the protective versus deleterious HLA-DPB1 alleles possess oppositely charged glutamic acid rather than lysine residues at position 69 in binding pocket 4, factors that may influence peptide affinities for HLA-DPB1[ 9].
The surface representation suggests that like PTP1B, HD-PTP has an open binding pocket in its active site that may allow phosphate binding.
