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

doi:10.1093/nar/gkz1224

	Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase
	Nguyen, Phuong D. M.1,2; Zheng, Jie 3,11; Gremminger, Thomas J.1; Qiu, Liming 4; Zhang, Dong 5; Tuske, Steve 6,7,10; Lange, Margaret J.8; Griffin, Patrick R.3; Arnold, Eddy 6,7; Chen, Shi-Jie 1,5,9
刊名	NUCLEIC ACIDS RESEARCH
	2020-03-18
卷号	48 期号:5 页码:2709-2722
ISSN号	0305-1048
DOI	10.1093/nar/gkz1224
通讯作者	Burke, Donald H.(burkedh@missouri.edu)
英文摘要	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.
资助项目	National Institutes of Health (NIH)[R01AI074389] ; National Institutes of Health (NIH)[R01GM109980] ; National Institutes of Health (NIH)[R01GM117059] ; National Institutes of Health (NIH)[R01GM063732] ; National Institutes of Health (NIH)[R37AI026790] ; National Institutes of Health (NIH)[U54 GM103368] ; National Institutes of Health (NIH)[R01AI150460] ; NIH[R01AI074389]
WOS关键词	VIRUS TYPE-1 HIV-1 ; STRANDED-DNA ; H DOMAIN ; MOLECULAR-MECHANISMS ; ANGSTROM RESOLUTION ; CRYSTAL-STRUCTURE ; RIBONUCLEASE-H ; ACTIVE-SITE ; INHIBITORS ; INTEGRASE
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	OXFORD UNIV PRESS
WOS记录号	WOS:000525957100042
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281002]
专题	中国科学院上海药物研究所
通讯作者	Burke, Donald H.
作者单位	1.Univ Missouri, Dept Biochem, Columbia, MO 65211 USA 2.Univ Missouri, Bond Life Sci Ctr, Columbia, MO 65211 USA 3.Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA 4.Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO 65211 USA 5.Univ Missouri, Dept Phys & Astron, Columbia, MO 65211 USA 6.Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA 7.Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA 8.Univ Missouri, Dept Mol Microbiol & Immunol, Columbia, MO 65211 USA 9.Univ Missouri, MU Inst Data Sci & Informat, Columbia, MO 65211 USA 10.Amicus Therapeut, Gene Therapy Ctr Excellence, 3675 Market St, Philadelphia, PA 19104 USA
推荐引用方式 GB/T 7714	Nguyen, Phuong D. M.,Zheng, Jie,Gremminger, Thomas J.,et al. Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase[J]. NUCLEIC ACIDS RESEARCH,2020,48(5):2709-2722.
APA	Nguyen, Phuong D. M..,Zheng, Jie.,Gremminger, Thomas J..,Qiu, Liming.,Zhang, Dong.,...&Burke, Donald H..(2020).Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase.NUCLEIC ACIDS RESEARCH,48(5),2709-2722.
MLA	Nguyen, Phuong D. M.,et al."Binding interface and impact on protease cleavage for an RNA aptamer to HIV-1 reverse transcriptase".NUCLEIC ACIDS RESEARCH 48.5(2020):2709-2722.