Figure 1.
Structures of adefovir, (R)-tenofovir and (S)-tenofovir.
PDB coordinates of Mg-adefovir and Mg-(R)-tenofovir were taken from the PDBids 1ZOT and 3FKB, respectively. (S)-tenofovir was created via CORINA. Mg-ions near the red phosphate moieties are in green. Arrows indicate the carbon atom linking the purine group with the phosphates (a center of asymmetry in tenofovir). Numbers in white are the total protein-ligand energy interaction values indicating the affinity to wt HBV reverse transcriptase.
Table 1.
Protein-ligand energy interaction values of HBV-RT wildtype and mutants associated with adefovir-resistance.
Table 2.
Single nucleotide mutations leading to AA replacements in HBV-RT associated with adefovir resistence.
Figure 2.
Clustering analysis of in silico modeled HBV RT with crystal models of polymerase.
The 3D-structure of HBV-RT and the PDB coordinate files of the other polymerases were aligned and the pairwise RMSD values were put into a distance matrix for tree construction. HBV-RT is indicated in bold-face. The scale bar represents a RMSD value of 1. The date is added to anticipate future additions to the PDB database.
Figure 3.
Binding of deoxyribonucleotidetriphosphates to wt HBV reverse transcriptase.
The Mg-dNTPs are in red-colored, space-filled format. Other space-filled residues indicate the YMDD motif sequence marking the HBV-RT nucleotide binding site. Numbers in white are the total protein-ligand energy interaction values indicating the Mg-dNTP affinity to wt HBV-RT.
Figure 4.
Binding of tenofovir and adefovir to wt HBV reverse transcriptase.
Mg-adefovir (left panel, red cartoon) binds close to YMDD (space-filled format) in the large central pocket of HBV-RT. Mg-tenofovir (right panel, red cartoon) binds in a small pocket at the backside of YMDD (space-filled format).
Figure 5.
Sequential docking of dATP, dGTP, and adefovir (left panel) or tenofovir (right panel) into the HBV-RT structure carrying S78T & A181V amino acid replacements.
T78 and V181 are in hot-pink. YMDD is indicated by space-filling. Mg-adefovir and Mg-tenofovir are in red cartoon format. Mg-dATP is white and Mg-dGTP is blue colored. Total protein-ligand energy interaction values (Kcal/mol) are −9.38 (dATP), −7.65 (dGTP), −7.55 (tenofovir) and −5.07 (adefovir).