Structural basis for high-affinity fluorophore binding and activation by RNA Mango

Trachman, Robert J.; Demeshkina, N.; Lau, Matthew W.L.; Panchapakesan, Shanker Shyam S.; Jeng, Sunny; Unrau, Peter J.; Ferré-D′Amaré, A.R.

doi:10.1038/nchembio.2392

Cited by 109 publications

(128 citation statements)

References 47 publications

(74 reference statements)

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“…In turn, these facilitate formation of stable parallel topologies with shorter loops . However, several exceptions have appeared , including that of a 97‐nt RNA fluorogenic aptamer which bears a distinctive antiparallel G‐quadruplex (Fig. A) at an internal bulge separating two helical domains .…”

Section: G‐quadruplex Core Structuresmentioning

confidence: 99%

The diverse structural landscape of quadruplexes

et al. 2019

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G‐quadruplexes are secondary structures formed in G‐rich sequences in DNA and RNA. Considerable research over the past three decades has led to in‐depth insight into these unusual structures in DNA. Since the more recent exploration into RNA G‐quadruplexes, such structures have demonstrated their in cellulo existence, function and roles in pathology. In comparison to Watson‐Crick‐based secondary structures, most G‐quadruplexes display highly redundant structural characteristics. However, numerous reports of G‐quadruplex motifs/structures with unique features (e.g. bulges, long loops, vacancy) have recently surfaced, expanding the repertoire of G‐quadruplex scaffolds. This review addresses G‐quadruplex formation and structure, including recent reports of non‐canonical G‐quadruplex structures. Improved methods of detection will likely further expand this collection of novel structures and ultimately change the face of quadruplex‐RNA targeting as a therapeutic strategy.

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Section: G‐quadruplex Core Structuresmentioning

confidence: 99%

The diverse structural landscape of quadruplexes

et al. 2019

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“…To reveal the mechanism of fluorescence activation by the Mango, the crystallization of Mango-TO1 complex was determined. The co-crystal structure of Mango-TO1 revealed a three-tiered Gquadruplex that included three antiparallel quinine residues connected to an A-form duplex through a GAAA tetraloop-like junction [32]. The fluorophore bound on one of the flat faces of the G-quadruplex, stabilized the Mango-TO binding for fluorescence.…”

Section: Mangomentioning

confidence: 99%

“…S. Yoon, J.J. Rossi / Advanced Drug Delivery Reviews 134 (2018)[22][23][24][25][26][27][28][29][30][31][32][33][34][35] …”

mentioning

confidence: 99%

Aptamers: Uptake mechanisms and intracellular applications

Yoon

Rossi

2018

Advanced Drug Delivery Reviews

115

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The structural flexibility and small size of aptamers enable precise recognition of cellular elements for imaging and therapeutic applications. The process by which aptamers are taken into cells depends on their targets but is typically clathrin-mediated endocytosis or macropinocytosis. After internalization, most aptamers are transported to endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and occasionally mitochondria and autophagosomes. Intracellular aptamers, or "intramers," have versatile functions ranging from intracellular RNA imaging, gene regulation, and therapeutics to allosteric modulation, which we discuss in this review. Immune responses to therapeutic aptamers and the effects of G-quadruplex structure on aptamer function are also discussed.

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“…Nevertheless, despite this improved folding capacity, iSpinach still shares the complex structural organization of the Spinach family (i.e., a mixed-base quadruplex core surrounded by two flanking A-form helices), characterized by a complex connectivity. Whereas building the dye-binding pocket around a base quadruple is common to several fluorogenic RNA aptamers (Trachman et al 2017b), the use of more conventional G-quadruplex folding with short propeller arms may enable the connectivity of these molecules to be simplified by using, for instance, a simple GNRA-derived motif as recently described for Mango RNA (Trachman et al 2017a). Therefore, future work may lead to the isolation of fluorogenic aptamers with folding properties even surpassing that of iSpinach.…”

Section: Structural Comparative Analysis Of Ispinach and Spinach Aptamentioning

confidence: 99%

Crystal structure and fluorescence properties of the iSpinach aptamer in complex with DFHBI

Fernández-Millán¹,

Autour²,

Ennifar³

et al. 2017

RNA

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Fluorogenic RNA aptamers are short nucleic acids able to specifically interact with small molecules and strongly enhance their fluorescence upon complex formation. Among the different systems recently introduced, Spinach, an aptamer forming a fluorescent complex with the 3,5-difluoro-4-hydroxybenzylidene imidazolinone (DFHBI), is one of the most promising. Using random mutagenesis and ultrahigh-throughput screening, we recently developed iSpinach, an improved version of the aptamer, endowed with an increased folding efficiency and thermal stability. iSpinach is a shorter version of Spinach, comprising five mutations for which the exact role has not yet been deciphered. In this work, we cocrystallized a reengineered version of iSpinach in complex with the DFHBI and solved the X-ray structure of the complex at 2 Å resolution. Only a few mutations were required to optimize iSpinach production and crystallization, underlying the good folding capacity of the molecule. The measured fluorescence half-lives in the crystal were 60% higher than in solution. Comparisons with structures previously reported for Spinach sheds some light on the possible function of the different beneficial mutations carried by iSpinach.

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Structural basis for high-affinity fluorophore binding and activation by RNA Mango

Cited by 109 publications

References 47 publications

The diverse structural landscape of quadruplexes

The diverse structural landscape of quadruplexes

Aptamers: Uptake mechanisms and intracellular applications

Crystal structure and fluorescence properties of the iSpinach aptamer in complex with DFHBI

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