Question

What happens in a Y181C mutation when HIV-1RT is introduced to nevirapine? In terms of the amino acid changes, conformational changes in the p66/p55 subdomains and in the fingers, palm of p66?

Answer 1

Nevirapine usually selects for Y181C when administered without a concomitant thymidine analogue. This mutation confers very high-level resistance (50- to 100-fold) to the drug. Y181C occurs in <5% of patients developing virological failure. Y181I/V have similar resistance effects. Mutation occurs in 13 amino acid positions in the palm subdomain of the p66 subunit of the HIV-1 RT structure.

The quaternary structure of HIV-Reverse Transcriptase (HIV-RT), is characterized by two peptide chains: the p66 and p51 subunits, each of which contains the "thumb", "fingers", "palm" and "connection" domains. The p66 domains are arranged in a way that grants them flexibility and catalytic function. The p66 palm, finger and thumb domains are oriented in a way that mimics that of a right hand, which allows the finger and thumb domains to remain in an open conformation (similar to an open hand) when unbound and switch to a closed conformation when bound to a template RNA strand, a primer, and nucleotides for polymerization (alternate view). It is these two conformations that allow the protein to switch between catalytic activity and its apo state. In the closed conformation, the finger and thumb domains clamp down onto the substrates to hold the strands in place over the palm.