Structure of an RNA Aptamer that Can Inhibit HIV-1 by Blocking Rev-Cognate RNA (RRE) Binding and Rev-Rev Association

Dearborn, Altaira D.; Eren, Elif; Watts, Norman R.; Palmer, Ira; Kaufman, Joshua D.; Steven, Alasdair C.; Wingfield, Paul T.

doi:10.1016/j.str.2018.06.001

Cited by 18 publications

(11 citation statements)

References 41 publications

(83 reference statements)

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“…The above-mentioned exceptions, where the protein–aptamer complex formation results in pronounced global conformational changes of the protein partner, include the NF-κB (p50) 2 homodimer–aptamer complex (PDB code 1OOA; ( 80 )) and the HIV-1 Rev–RNA aptamer complex (PDB code: 6CF2; ( 81 )). Compared to the NF-κB/DNA complex (PDB code 1NFK; ( 82 )), upon aptamer binding NF-κB (1OOA) undergoes an allosteric conformational change resulting in an open conformation between its N- and C-terminal domains.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer

Ptacek

Zhang

Qiu

et al. 2020

Nucleic Acids Research

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Prostate-specific membrane antigen (PSMA) is a well-characterized tumor marker associated with prostate cancer and neovasculature of most solid tumors. PSMA-specific ligands are thus being developed to deliver imaging or therapeutic agents to cancer cells. Here, we report on a crystal structure of human PSMA in complex with A9g, a 43-bp PSMA-specific RNA aptamer, that was determined to the 2.2 Å resolution limit. The analysis of the PSMA/aptamer interface allows for identification of key interactions critical for nanomolar binding affinity and high selectivity of A9g for human PSMA. Combined with in silico modeling, site-directed mutagenesis, inhibition experiments and cell-based assays, the structure also provides an insight into structural changes of the aptamer and PSMA upon complex formation, mechanistic explanation for inhibition of the PSMA enzymatic activity by A9g as well as its ligand-selective competition with small molecules targeting the internal pocket of the enzyme. Additionally, comparison with published protein–RNA aptamer structures pointed toward more general features governing protein-aptamer interactions. Finally, our findings can be exploited for the structure-assisted design of future A9g-based derivatives with improved binding and stability characteristics.

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Section: Discussionmentioning

confidence: 99%

Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer

Ptacek

Zhang

Qiu

et al. 2020

Nucleic Acids Research

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“…This aptamer suppressed HIV production from HIV proviral clones. Finally, Dearborn et al identified small RNA aptamers that competed with the RRE for Rev binding, and predicted the structure of aptamer–Rev binding complex [ 205 ]. The structure showed that Rev’s ARM interacts with the major groove of the aptamer.…”

Section: Aptamers For Single-stranded Rna Viruses With Dna Intermediatementioning

confidence: 99%

“…Aptamers for targeting the HIV Rev protein The HIV Rev protein mediates nuclear export of unspliced and partially spliced viral RNAs. Rev assembles on a 351-nt Rev response element (RRE) within viral transcripts and induces the host's nuclear export mechanism [205]. Aptamers can act as a Rev-binding element (RBE) and therefore anti-Rev aptamers are likely a good strategy for anti-HIV therapeutics.…”

Section: Therapeutic Aptamers For Targeting Hiv Viral Proteinsmentioning

confidence: 99%

Aptamers for Anti-Viral Therapeutics and Diagnostics

Kim

Lee

2021

IJMS

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Viral infections cause a host of fatal diseases and seriously affect every form of life from bacteria to humans. Although most viral infections can receive appropriate treatment thereby limiting damage to life and livelihood with modern medicine and early diagnosis, new types of viral infections are continuously emerging that need to be properly and timely treated. As time is the most important factor in the progress of many deadly viral diseases, early detection becomes of paramount importance for effective treatment. Aptamers are small oligonucleotide molecules made by the systematic evolution of ligands by exponential enrichment (SELEX). Aptamers are characterized by being able to specifically bind to a target, much like antibodies. However, unlike antibodies, aptamers are easily synthesized, modified, and are able to target a wider range of substances, including proteins and carbohydrates. With these advantages in mind, many studies on aptamer-based viral diagnosis and treatments are currently in progress. The use of aptamers for viral diagnosis requires a system that recognizes the binding of viral molecules to aptamers in samples of blood, serum, plasma, or in virus-infected cells. From a therapeutic perspective, aptamers target viral particles or host cell receptors to prevent the interaction between the virus and host cells or target intracellular viral proteins to interrupt the life cycle of the virus within infected cells. In this paper, we review recent attempts to use aptamers for the diagnosis and treatment of various viral infections.

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“…Another work showed that the major groove of the aptamer was bound to the arginine-rich helix domain of the target protein, Rev ( Figure 2 b), ending up with several contacts additional to those formed by the wild-type RNA. Once bound with the target protein, the aptamer would hamper Rev oligomerization at the interface [ 72 ].…”

Section: Interfaces Between Aptamer–protein Complexesmentioning

confidence: 99%

Structural Biology for the Molecular Insight between Aptamers and Target Proteins

Zhang

Chen

Liu

et al. 2021

IJMS

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Aptamers are promising therapeutic and diagnostic agents for various diseases due to their high affinity and specificity against target proteins. Structural determination in combination with multiple biochemical and biophysical methods could help to explore the interacting mechanism between aptamers and their targets. Regrettably, structural studies for aptamer–target interactions are still the bottleneck in this field, which are facing various difficulties. In this review, we first reviewed the methods for resolving structures of aptamer–protein complexes and for analyzing the interactions between aptamers and target proteins. We summarized the general features of the interacting nucleotides and residues involved in the interactions between aptamers and proteins. Challenges and perspectives in current methodologies were discussed. Approaches for determining the binding affinity between aptamers and target proteins as well as modification strategies for stabilizing the binding affinity of aptamers to target proteins were also reviewed. The review could help to understand how aptamers interact with their targets and how alterations such as chemical modifications in the structures affect the affinity and function of aptamers, which could facilitate the optimization and translation of aptamers-based theranostics.

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Structure of an RNA Aptamer that Can Inhibit HIV-1 by Blocking Rev-Cognate RNA (RRE) Binding and Rev-Rev Association

Cited by 18 publications

References 41 publications

Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer

Structural basis of prostate-specific membrane antigen recognition by the A9g RNA aptamer

Aptamers for Anti-Viral Therapeutics and Diagnostics

Structural Biology for the Molecular Insight between Aptamers and Target Proteins

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