Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase

Nguyen, Phuong M.; Zheng, Jie; Gremminger, Thomas J.; Qiu, Liming; Zhang, Dong; Tuske, Steve; Lange, Margaret J.; Griffin, Patrick R.; Arnold, Eddy; Chen, Shi-Jie; Zou, Xiaoqin; Heng, Xiao; Burke, Donald H.

doi:10.1093/nar/gkz1224

Title: Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase

Journal Article · Thu Jan 16 00:00:00 EST 2020 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkz1224· OSTI ID:1616611

Nguyen, Phuong M. ^[1]; Zheng, Jie ^[2]; Gremminger, Thomas J. ^[1]; Qiu, Liming ^[1];

^[1]; Tuske, Steve ^[3]; Lange, Margaret J. ^[1];

^[2]; Arnold, Eddy ^[3];

^[1]; Zou, Xiaoqin ^[1]; Heng, Xiao ^[1];

^[1]

Univ. of Missouri, Columbia, MO (United States)
The Scripps Research Inst., Jupiter, FL (United States)
Rutgers Univ., Piscataway, NJ (United States)

RNA aptamers that bind HIV-1 reverse transcriptase (RT) inhibit RT in enzymatic and viral replication assays. Some aptamers inhibit RT from only a few viral clades, while others show broad-spectrum inhibition. Biophysical determinants of recognition specificity are poorly understood. We investigated the interface between HIV-1 RT and a broad–spectrum UCAA-family aptamer. SAR and hydroxyl radical probing identified aptamer structural elements critical for inhibition and established the role of signature UCAA bulge motif in RT-aptamer interaction. HDX footprinting on RT ± aptamer shows strong contacts with both subunits, especially near the C-terminus of p51. Alanine scanning revealed decreased inhibition by the aptamer for mutants P420A, L422A and K424A. 2D proton nuclear magnetic resonance and SAXS data provided constraints on the solution structure of the aptamer and enable computational modeling of the docked complex with RT. Surprisingly, the aptamer enhanced proteolytic cleavage of precursor p66/p66 by HIV-1 protease, suggesting that it stabilizes the productive conformation to allow maturation. These results illuminate features at the RT-aptamer interface that govern recognition specificity by a broad-spectrum antiviral aptamer, and they open new possibilities for accelerating RT maturation and interfering with viral replication.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: R01AI074389; R01GM109980; R01GM117059; R01GM063732; R37AI026790; U54 GM103368; R01AI150460

OSTI ID:: 1616611

Journal Information:: Nucleic Acids Research, Vol. 48, Issue 5; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 18 works

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