 Binding of NNRTI to HIV-1 RT makes the p66 thumb domain hyper extended because it induces rotamer conformation changes in amino acid residues Tyr-181 and Tyr-188.This affects the catalytic activity of the enzyme and blocks the HIV-1 replication by inhibiting the polymerase active site of the RT's p66 subunit.The global conformational change additionally destabilizes the enzyme on its nucleic acid template and reduces its ability to bind nucleotides.