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Publication Abstract from PubMed

Reverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNA(Lys)(3) primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC-nevirapine, and RTIC-efavirenz complexes at 2.8, 3.1, and 2.9 A, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA-tRNA(Lys)(3) initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.

High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs.,Ha B, Larsen KP, Zhang J, Fu Z, Montabana E, Jackson LN, Chen DH, Puglisi EV Nat Commun. 2021 May 4;12(1):2500. doi: 10.1038/s41467-021-22628-9. PMID:33947853^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.