Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Role of Conserved Water Molecules in Binding of Thyroxin and Analogs Inhibitors to Human Transthyretin: A Study On Water-Mimic Inhibitor Design.
Transthyretin (TTR) is a very important protein associated with the transportation of thyroxin hormone and vitamin-A in the serum as well as in ceribro-spinal-fluid of human (1). The protein is also responsible to cause amyloid diseases like FAP (Familial Amyloidotic Poly-neuropathy) and SSA (Senile systematic Amyloidosis) due to formation of amyloid fibrils (2, 3) by the protein and their deposition in extra cellular matrixes and tissues in human body (4). Simulation of different X-ray structures of TTR [available as dimer in Protein Data Bank, Resolution 1.3-2.0Å] and their water dynamics have revealed the presence of six conserved water molecules in the buried core of A-chain, 4- in B-chain and 6- in the interface of the dimer. Among these conserved water molecules, one in each monomer seems to play an important role in the thyroxin binding with the protein. Comparative analysis of unliganded TTR and TTR-Thyroxin complex structures (5) and their water molecular dynamics reveal that in the unliganded structures the conserved water molecule forms H-bond with the side-chains of two important residues, Ser-117 and Thr-119, of the thyroxin binding pocket (6). The Ser-Thr bound conserved water molecule seems to migrate when the thyroxin molecule enters in the pocket and forms complex with the protein. Again, during migration of that water molecule, side chains of the respective Ser-117 and Thr-119 adopt a trans like conformation which stereo-chemically assist the thyroxin molecule to occupy the specific binding pocket of TTR [Figure1]. The positional invariance of that water molecule with the 5’-iodine atom of thyroxin molecule seems to be interesting. These results may provide further insight and complementary information into thyroxin/inhibitor (thyroxin analog) binding chemistry, which may be used as a new strategy in search of a new effective TTR-inhibitor design.
Department of Chemistry, National Institute of Technology-Durgapur, West Bengal,
Durgapur –713209, India
Figure 1. Interaction of conserved water molecule ( W ) with Ser 117 and Thr 119 in unliganded form of Protein. Transition of TTR-thyroxin complex to Unliganded TTR.