Uridine analogs of 2′,5′-oligoadenylates: On the biological role of the middle base of 2-5A trimer

Kitade, Yukio; Alster, D.; Pabuççuoğlu, Aysun; Torrence, Paul F.

doi:10.1016/0045-2068(91)90054-s

Cited by 12 publications

(4 citation statements)

References 15 publications

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“…Interestingly, the second adenine ring was less important for the activation of RNase L ([12] and [13]) (Imai et al , 1985). Use of uridine analogs of 2‐5A also produced similar results (Kitade et al , 1991a). These results are consistent with our structure showing that the second adenine ring (Ade2) is recognized by only a single hydrogen bond with the nonconserved side chain of Tyr135 (Figures 3A and 5C).…”

Section: Discussionmentioning

confidence: 64%

Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L

Tanaka

Nakanishi

Kusakabe

et al. 2004

EMBO J

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An interferon-induced endoribonuclease, ribonuclease L (RNase L), is implicated in both the molecular mechanism of action of interferon and the fundamental control of RNA stability in mammalian cells. RNase L is catalytically active only after binding to an unusual activator molecule containing a 5 0 -phosphorylated 2 0 ,5 0 -linked oligoadenylate (2-5A), in the N-terminal half. Here, we report the crystal structure of the N-terminal ankyrin repeat domain (ANK) of human RNase L complexed with the activator 2-5A. This is the first structural view of an ankyrin repeat structure directly interacting with a nucleic acid, rather than with a protein. The ANK domain folds into eight ankyrin repeat elements and forms an extended curved structure with a concave surface. The 2-5A molecule is accommodated at a concave site and directly interacts with ankyrin repeats 2-4. Interestingly, two structurally equivalent 2-5A binding motifs are found at repeats 2 and 4. The structural basis for 2-5A recognition by ANK is essential for designing stable 2-5As with a high likelihood of activating RNase L.

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Section: Discussionmentioning

confidence: 64%

Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L

Tanaka

Nakanishi

Kusakabe

et al. 2004

EMBO J

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“…Trimeric 2–5A (ppp5′A2′p5′A2′p5′A) introduced into L929 cells directly triggered apoptosis whereas mock transfection of cells did not (Table 2 ). Moreover, apoptosis was not triggered by the structurally related analogue-inhibitor, ppp5′A2′p5′ A2′p5′U ( 17 ) (Table 2 ), which can bind to RNase L but is 10 5 -fold less effective as an activator due to the missing N1/N6 domain of the third adenine ring of parent 2–5A ( 18 ). These results correlate an increase in RNase L enzymatic activity with an induction in apoptosis.…”

Section: Resultsmentioning

confidence: 99%

A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System

Castelli

Hassel

Wood

et al. 1997

The Journal of Experimental Medicine

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254

176

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The 2–5A system contributes to the antiviral effect of interferons through the synthesis of 2–5A and its activation of the ribonuclease, RNase L. RNase L degrades viral and cellular RNA after activation by unique, 2′–5′ phosphodiester-linked, oligoadenylates [2–5A, (pp)p5′ A2′(P5′A2′)]n, n ⩾2. Because both the 2–5A system and apoptosis can serve as viral defense mechanisms and RNA degradation occurs during both processes, we investigated the potential role of RNase L in apoptosis. Overexpression of human RNase L by an inducible promoter in NIH3T3 fibroblasts decreased cell viability and triggered apoptosis. Activation of endogenous RNase L, specifically with 2–5A or with dsRNA, induced apoptosis. Inhibition of RNase L with a dominant negative mutant suppressed poly (I)·poly (C)–induced apoptosis in interferon-primed fibroblasts. Moreover, inhibition of RNase L suppressed apoptosis induced by poliovirus. Thus, increased RNase L levels induced apoptosis and inhibition of RNase L activity blocked viral-induced apoptosis. Apoptosis may be one of the antiviral mechanisms regulated by the 2–5A system.

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“…As a result of these studies, structural requirements emerged that are important for RNase L activation (reviewed in [4,13]). Adenine bases were modified in several positions [14,15], or even substituted by other base moieties [15,16]. Substitution of H-8 in adenine with a Br atom [17], a methyl group [18], or a hydroxyl group [19] seems to change mainly the base-to-ribose orientation, which may have implications for endonuclease binding capacity.…”

Section: (2′-5′)oligoadenylates Modified On the Heterocyclic Basementioning

confidence: 99%

“…Substitution of H-8 in adenine with a Br atom [17], a methyl group [18], or a hydroxyl group [19] seems to change mainly the base-to-ribose orientation, which may have implications for endonuclease binding capacity. Despite the assumption of minor role of the central adenosine residue [14], its substitution by uridine reduces binding and activation significantly [16]. These studies have generally shown that the presence of adenosine in all positions of the 2-5A chain is crucial for the mediator activity and minimal modifications of heterocyclic bases might be acceptable.…”

Section: (2′-5′)oligoadenylates Modified On the Heterocyclic Basementioning

confidence: 99%

Modified (2′,5′)Oligonucleotides: The Influence of Structural and Steriochemical Factors on Biological and Immunotropic Activity

Kalinichenko¹

2023

Oligonucleotides - Overview and Applications

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The synthesis of a large number of analogs of natural 2-5A and the results of studies to clarify the relationship between the structure and spatial organization (stereochemistry) and the biological properties of analogs 2-5A have convincingly demonstrated that by changing the structure and/or stereochemistry of molecules, it is possible to achieve either strengthening of known properties or giving new ones. The replacement of the adenosine fragment with 1-deazaadenosine (c1A) or 3-deazaadenosine (c3A) at various positions of the 2-5A chain demonstrated the role of each of the nitrogen atoms of the adenine heterocycle in the processes of binding and activation of RNase L. The use of conformationally rigid fluorodeoxyadenylates in enzymatic reactions made it possible to differentiate the role of structural and stereochemical factors and demonstrate the influence of molecules’ stereochemistry on their biological properties. Oligomers with ribo-[(2′,5′)A2ARA] and lixo-[(2′,5′)A2ALA] conformation in the (A3) terminal fragment showed activity against diseases associated with disorders of T-cell immunity, autoimmune diseases, viral infections, lymphocytic malignant transformations, prevention of transplant rejection after bone marrow transplantation and, possibly, in the treatment of complications associated with the reaction of the transplanted tissue and the recipient’s tissue.

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Uridine analogs of 2′,5′-oligoadenylates: On the biological role of the middle base of 2-5A trimer

Cited by 12 publications

References 15 publications

Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L

Structural basis for recognition of 2′,5′-linked oligoadenylates by human ribonuclease L

A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System

Modified (2′,5′)Oligonucleotides: The Influence of Structural and Steriochemical Factors on Biological and Immunotropic Activity

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