7KJX

Structure of HIV-1 reverse transcriptase initiation complex core with nevirapine

Summary for 7KJX

• Entry DOI: 10.2210/pdb7kjx/pdb
• EMDB information: 22901
• Descriptor: Reverse transcriptase/ribonuclease H, reverse transcriptase p51 subunit, HIV-1 viral RNA fragment, ... (6 entities in total)
• Functional Keywords: reverse transcriptase, rna, protein-rna complex, trna, polymerase, viral protein, viral protein-rna complex, viral protein/rna
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); More
• Total number of polymer chains: 4
• Total formula weight: 132048.61

Authors

Ha, B.,Larsen, K.P.,Zhang, J.,Fu, Z.,Montabana, E.,Jackson, L.N.,Chen, D.H.,Puglisi, E.V. (deposition date: 2020-10-26, release date: 2021-03-17, Last modification date: 2024-10-23)

Primary citation

Ha, B.,Larsen, K.P.,Zhang, J.,Fu, Z.,Montabana, E.,Jackson, L.N.,Chen, D.H.,Puglisi, E.V.
High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs.
Nat Commun, 12:2500-2500, 2021

PubMed Abstract: 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 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 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA-tRNA 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.

PubMed: 33947853
DOI: 10.1038/s41467-021-22628-9

Experimental method

ELECTRON MICROSCOPY (3.1 Å)