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 3'-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 3'-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.
Al-Mawsawi
Laith Q
LQ
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Sechi
Mario
M
Neamati
Nouri
N
D019943:Amino Acid Substitution; D001665:Binding Sites; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D006801:Humans; D011487:Protein Conformation; D012694:Serine; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D019428:HIV Integrase Inhibitors; D012694:Serine; D019427:HIV Integrase