Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Conserved Water Mediated Inter-Domain Recognition in IMPDH-II (human)
The inosine monophosphate dehydrogenase is a key enzyme in the de novo biosynthesis pathway and controls the guanine nucleotides pools (1). Two isoforms of human IMPDH have been identified and designated as type I (house-keeping role), which is found in normal resting cells, whereas the type II is selectively up regulated during cellular proliferation, thus, considering it an excellent target for the development and designing the anti cancer and immunosuppressive drugs (2). Interestingly, IMPDH II has two highly stereospecific conserved domains that recognized the mononucleotide ligands (the IMP or its structural analogs CPR, RVP can bind) and dinucleotide ligands (NAD or its structural analogs SAE and MAD), respectively (3). However, only three X-ray structures of human IMPDH-II enzymes (1B3O, 1NFB, and 1NF7) (4, 5) are available in the Protein Databank with partial disorder at ∼25% of the total 514 residues. So, the modeling and water dynamic studies are essential to investigate the detail interdomain recognition in the protein. Our computational results revealed that both the (mono- and di-nucleotide) ligand binding domains are recognized by conserved water molecule (WM) (6). To anchor these two domain, nature placed the Arg 322 in such a steoreochemical orientation that the NH1 atom (of Arg 322) is recognized the di-nucleotide binding domain via the conserved water molecule (WC), whereas the NH2 nitrogen atom has also played a key role to recognize the mono-nucleotide binding domain through the another conserved water molecule (WL). The conserved water molecule (WM) bridged these two domains through the eight center H-bonding patterns. These water mediated interactinal patterns may suggest the new structural insight of human IMPDH II proteins which may obsolete in non-human IMPDH.
So both the mono and di-nucleotide ligand binding domains of human IMPDH II may thought to be stabilized by the R 322 through a conserved water molecular triad (WC, WM, and WL). The proposed water molecular triad in the protein is shown in the given figure.
Hridoy R. Bairagya*
Department of Chemistry
Reference and Footnotes