HIV-1 reverse transcriptase lacks 3'→5' exonuclease proofreading activity, resulting in a high mutation rate. Among the non-nucleoside reverse transcriptase inhibitors (NNRTIs), resistance develops rapidly with monotherapy because a single mutation at which critical binding site residue confers class resistance?

• A K65R in the nucleotide-binding site
• B K103N (lysine to asparagine at codon 103) in the NNRTI allosteric pocket ✓
• C M184V in the YMDD motif of reverse transcriptase
• D D30N in the protease flap region

Explanation

NNRTIs bind to a hydrophobic allosteric pocket adjacent to (but distinct from) the RT active site, locking the enzyme in an inactive conformation. The K103N mutation (and Y181C, Y188L) disrupts key binding contacts in this pocket, conferring broad resistance to first-generation NNRTIs (nevirapine, efavirenz) with a single substitution. M184V confers lamivudine/emtricitabine resistance; K65R is associated with tenofovir resistance; D30N is a protease inhibitor resistance mutation in nelfinavir.

Reference: Ananthanarayan & Paniker's Textbook of Microbiology, 11th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.