It is estimated that about 30–35 percent of proteins in the human proteome are integral membrane proteins. However, only a small fraction of membrane proteins, such as G-protein coupled receptors (GPCRs) and ion channels, have been considered as drug targets. A vast majority of membrane proteins are yet to be characterized in humans and other organisms. For example, many bacterial membrane proteins can be exploited as targets for anti-bacterial diseases. One such example is membrane proteins belonging to the family of formate/nitrate transporters (FNTs), which selectively transport monovalent anions such as formate, nitrite, lactate, and hydrosulphide. They are present in bacteria, archaea, and lower eukaryotes and are completely absent in humans. Under physiological conditions, they form pentamers. FNTs belonging to two subfamilies are uncharacterized and their substrate preference is not known.
The cover image of the February 25 issue of Biophysical Journal is an artistic rendering of the pentamer of the uncharacterized FNT homolog from E.coli embedded in a POPE lipid bilayer. The lipid head groups are shown as translucent clouds. The conserved Glu residues near the extracellular and cytoplasmic vestibule regions appear as yellow Van der Waals (VDW) spheres. The substrates ammonia, formate, and formic acid are shown in stick models with standard colors used to represent the atoms. The plot next to it shows the free-energy profile for formate (red), ammonia (blue), and formic acid (yellow) permeation through E.coli FNT monomer with protonated central histidine. Our computational study strongly suggests the E.coli FNT homolog is not likely to transport anions due to the presence or absence of specific charged residues at the entrance of the channel. We propose the E.coli FNT is most likely to transport neutral molecules or even cations. This image was created by Ankita Gupta using Visual Molecular Dynamics software and edited using Photoshop.
One of the main research interests of our lab is to understand the selectivity and transport mechanism of membrane channels and transporters using computational approaches. This study shows different subgroups of membrane channels belonging to the same family can have distinct preference to transport substrates and the substrates can be oppositely charged or neutral.
Additional information regarding our work can be found at: http://home.iitk.ac.in/~rsankar
— Mishtu Mukherjee, Ankita Gupta, and Ramasubbu Sankararamakrishnan