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Selective recognition of human telomeric G-quadruplex with designed peptide via hydrogen bonding followed by base stacking interactions.

ABSTRACT: We described a novel synthetic peptide in which a glutamine residue binds through hydrogen bonding to a guanine-base and a trytophan residue intercalates with K⁺ resulting in stabilization of a human telomeric G-quadruplex with high selectivity over its complementary c-rich strand and a double-stranded DNA and its complementary C-rich strand. This peptide offers great potential for cancer treatment by inhibiting the telomere extension by telomerase.

SUBMITTER: Tyagi S

PROVIDER: S-EPMC9076235 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Selective recognition of human telomeric G-quadruplex with designed peptide <i>via</i> hydrogen bonding followed by base stacking interactions.

Tyagi Shikhar S Saxena Sarika S Saxena Sarika S Kundu Nikita N Sharma Taniya T Chakraborty Amlan A Kaur Sarvpreet S Miyoshi Daisuke D Shankaraswamy Jadala J

RSC advances 20191204 69

We described a novel synthetic peptide in which a glutamine residue binds through hydrogen bonding to a guanine-base and a trytophan residue intercalates with K<sup>+</sup> resulting in stabilization of a human telomeric G-quadruplex with high selectivity over its complementary c-rich strand and a double-stranded DNA and its complementary C-rich strand. This peptide offers great potential for cancer treatment by inhibiting the telomere extension by telomerase. ...[more]

PMID: 35542665

Similar Datasets

Guanine base stacking in G-quadruplex nucleic acids.

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Selective G-quadruplex DNA recognition by a new class of designed cyanines.

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Project description:A face-to-face stacking of aromatic rings is an effective non-covalent strategy to build functional architectures, as elegantly exemplified with protein folding and polynucleotide assembly. However, weak, non-directional, and context-sensitive van der Waals forces pose a significant challenge if one wishes to construct well-organized π-stacks outside the confines of the biological matrix. To meet this design challenge, we have devised a rigid polycyclic template to create a non-collapsible void between two parallel oriented π-faces. In solution, these shape-persistent aromatic clips self-dimerize to form quadruple π-stacks, the thermodynamic stability of which is enhanced by self-complementary N–H···N hydrogen bonds, and finely regulated by the regioisomerism of the π-canopy unit. With assistance from sufficient electrostatic polarization of the π-surface and bifurcated hydrogen bonds, a small polyheterocyclic guest can effectively compete against the self-dimerization of the host to afford a triple π-stack inclusion complex. A combination of solution spectroscopic, X-ray crystallographic, and computational studies aided a detailed understanding of this cooperative vs competitive process to afford layered aromatics with extraordinary structural regularity and fidelity. Stacking aromatic molecules through π–π interactions is a useful strategy to create ordered layers of small molecules, but the weak and non-directional nature of these forces creates a challenge in achieving long-range structural ordering. Here, a rigid molecular template that facilitates the creation of a non-collapsible void between two parallel π-faces is designed, and a central N–H motif is shown to increase the thermodynamic stability of self-dimerized assemblies and host–guest complexes via N–H…N hydrogen bonds.

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Recognition and binding of human telomeric G-quadruplex DNA by unfolding protein 1.

Project description:The specific recognition by proteins of G-quadruplex structures provides evidence of a functional role for in vivo G-quadruplex structures. As previously reported, the ribonucleoprotein, hnRNP Al, and it is proteolytic derivative, unwinding protein 1 (UP1), bind to and destabilize G-quadruplex structures formed by the human telomeric repeat d(TTAGGG)n. UP1 has been proposed to be involved in the recruitment of telomerase to telomeres for chain extension. In this study, a detailed thermodynamic characterization of the binding of UP1 to a human telomeric repeat sequence, the d[AGGG(TTAGGG)3] G-quadruplex, is presented and reveals key insights into the UP1-induced unfolding of the G-quadruplex structure. The UP1-G-quadruplex interactions are shown to be enthalpically driven, exhibiting large negative enthalpy changes for the formation of both the Na(+) and K(+) G-quadruplex-UP1 complexes (ΔH values of -43 and -19 kcal/mol, respectively). These data reveal three distinct enthalpic contributions from the interactions of UP1 with the Na(+) form of G-quadruplex DNA. The initial interaction is characterized by a binding affinity of 8.5 × 10(8) M(-1) (strand), 200 times stronger than the binding of UP1 to a single-stranded DNA with a comparable but non-quadruplex-forming sequence [4.1 × 10(6) M(-1) (strand)]. Circular dichroism spectroscopy reveals the Na(+) form of the G-quadruplex to be completely unfolded by UP1 at a binding ratio of 2:1 (UP1:G-quadruplex DNA). The data presented here demonstrate that the favorable energetics of the initial binding event are closely coupled with and drive the unfolding of the G-quadruplex structure.

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Structural basis of G-quadruplex DNA recognition by the yeast telomeric protein Rap1.

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Dual recognition of the human telomeric G-quadruplex by a neomycin-anthraquinone conjugate.

Project description:The authors report the recognition of a G-quadruplex formed by four repeat human telomeric DNA with aminosugar intercalator conjugates. The recognition of the G-quadruplex through dual binding mode ligands significantly increased the affinity of ligands for the G-quadruplex. One such example is a neomycin-anthraquinone conjugate (2) which exhibited nanomolar affinity for the quadruplex, and the affinity of (2) is nearly 1000 fold higher for the human telomeric G-quadruplex DNA than its constituent units, neomycin and anthraquinone.

| S-EPMC3977216 | biostudies-literature

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