Computational modeling of a binding conformation of the intermediate L-histidinal to histidinol dehydrogenase

Histidinol dehydrogenase (HDH) is one of the enzymes involved in the L-hist idine biosynthesis pathway, HDH is a dimer that contains one Zn2+ ion in ea ch identical subunit. In this study, we predicted a possible binding confor mation of the intermediate L-histidinal, which is experimentally not known, using a computational modeling method and three potent HDH inhibitors whos e structures are similar to that of L-histidinal. At first, a set of the mo st probable active conformations of the potent inhibitors was determined us ing two different pharmacophore mapping techniques, the active analogue app roach and the distance comparison method. From the most probable active con formations of the three potent inhibitors, the common parts of the L-histid inal structure were extracted and refined by energy minimization to obtain the binding conformation of L-histidinal. This predicted conformation of L- histidinal agrees with an experimentally determined conformation of L-histi dine in a single crystal, suggesting that it is an experimentally acceptabl e conformation. The capability in this conformation to coordinate a Zn2+ io n was examined by comparing the spatial relative geometry of its functional groups with those of ligands that coordinate with a Zn2+ ion in Zn protein s of the Protein Data Bank. This comparison supported our predicted conform ation.