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TitleHigh-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 2500, Year 2021
Publish dateMay 4, 2021
AuthorsBetty Ha / Kevin P Larsen / Jingji Zhang / Ziao Fu / Elizabeth Montabana / Lynnette N Jackson / Dong-Hua Chen / Elisabetta Viani Puglisi /
PubMed AbstractReverse 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 ...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.
External linksNat Commun / PubMed:33947853 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.1 Å
Structure data

EMDB-22899, PDB-7kjv:
Structure of HIV-1 reverse transcriptase initiation complex core
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-22900, PDB-7kjw:
Structure of HIV-1 reverse transcriptase initiation complex core with efavirenz
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-22901, PDB-7kjx:
Structure of HIV-1 reverse transcriptase initiation complex core with nevirapine
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-BOG:
octyl beta-D-glucopyranoside / detergent*YM

ChemComp-EFZ:
(-)-6-CHLORO-4-CYCLOPROPYLETHYNYL-4-TRIFLUOROMETHYL-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-2-ONE / medication, antiretroviral*YM

ChemComp-NVP:
11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-B:2',3'-E][1,4]DIAZEPIN-6-ONE / medication, antiretroviral*YM

Source
  • human immunodeficiency virus 1
  • human immunodeficiency virus type 1 group m subtype b (isolate bh10)
  • homo sapiens (human)
Keywordsviral protein/RNA / reverse transcriptase / RNA / protein-RNA complex / tRNA / polymerase / viral protein-RNA complex / VIRAL PROTEIN

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