Single amino acid substitution in HIV-1 integrase catalytic core causes a dramatic shift in inhibitor selectivity

HIV-1 integrase (IN) mediates the insertion of viral
cDNA into the cell genome, a vital process for replication. This
step is catalyzed by two separate DNA reaction events, termed
30-processing and strand transfer. Here, we show that six inhibitors
from five structurally different classes of compounds display
a selectivity shift towards preferential strand transfer inhibition
over the 30-processing activity of IN when a single serine is
substituted at position C130. Even though IN utilizes the same
active site for both reactions, this finding suggests a distinct conformational
dissimilarity in the mechanistic details of each IN
catalytic event.