Spatial Matching Selectivity and Solution Structure of Organic–Metal Hybrid to Quadruplex–Duplex Hybrid

Liu, Liu‐Yi; Wang, Kang‐Nan; Liu, Wenting; Zeng, You‐Liang; Hou, Ming‐Xuan; Yang, Jing; Mao, Zong‐Wan

doi:10.1002/anie.202106256

Cited by 19 publications

(16 citation statements)

References 59 publications

(3 reference statements)

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“…[33] Another high-resolution structure with binding at the Q-D junction was determined for a conjugated ligand composed of a quadruplex-specific naphthalene diimide (NDI) core linked to a positively charged platinum coordination complex [Pt-(dien)(py)]. [36] In close correspondence to the present indoloquinoline binding, the NDI ring system was found to be sandwiched between interfacial outer tetrad and neighboring base pair of a quadruplex with a lateral duplex stem-loop. Specific binding was further promoted by the platinum coordinated sidechain, interacting within the duplex minor groove through hydrogen bonds and electrostatic interactions.…”

Section: Discussionmentioning

confidence: 98%

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Vianney

Weisz

2022

Chemistry A European J

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Quadruplex-duplex (Q-D) junctions are increasingly considered promising targets for medicinal and technological applications. Here, a Q-D hybrid with a hairpin-type snapback loop coaxially stacked onto the quadruplex 3'-outer tetrad was designed and employed as a target structure for the indoloquinoline ligand SYUIQ-5. NMR spectral analysis demonstrated high-affinity binding of the ligand at the quadruplex-duplex interface with association constants determined by isothermal titration calorimetry of about 10 7 M À 1 and large exothermicities ΔH°of À 14 kcal/mol in a 120 mM K + buffer at 40 °C. Determination of the ligand-bound hybrid structure revealed intercalation of SYUIQ-5 between 3'-outer tetrad and the neighboring CG base pair, maximizing π-π stacking as well as electrostatic interactions with guanine carbonyl groups in close vicinity to the positively charged protonated quinoline nitrogen of the tetracyclic indoloquinoline. Exhibiting considerable flexibility, the SYUIQ-5 sidechain resides in the duplex minor groove. Based on comparative binding studies with the non-substituted N5-methylated indoloquinoline cryptolepine, the sidechain is suggested to confer additional affinity and to fix the alignment of the intercalated indoloquinoline aromatic core. However, selectivity for the Q-D junction mostly relies on the geometry and charge distribution of the indoloquinoline ring system. The presented results are expected to provide valuable guidelines for the design of ligands specifically targeting Q-D interfaces.

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Section: Discussionmentioning

confidence: 98%

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Vianney

Weisz

2022

Chemistry A European J

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“…We note that many small-molecule DNA/RNA complexes fold into duplex–quadruplex structures, such as quadruplex–duplex junction–ligand complexes, − and fluorogenic RNA aptamer–ligand complexes. − However, the interaction mode between DNA/RNA and the ligand in these complexes is different from that in the OBA33–OTA complex. G-Quadruplexes in these complexes are directly involved in the DNA/RNA–ligand interaction through the stacking interaction between the ligand and the G-quartet layer.…”

Section: Discussionmentioning

confidence: 94%

Structural Insights into the Mechanism of High-Affinity Binding of Ochratoxin A by a DNA Aptamer

Jie

et al. 2022

J. Am. Chem. Soc.

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A 36-mer guanine (G)-rich DNA aptamer (OBA36) is able to distinguish one atomic difference between ochratoxin analogues A (OTA) and B (OTB), showing prominent recognition specificity and affinity among hundreds of aptamers for small molecules. Why OBA36 has >100-fold higher binding affinity to OTA than OTB remains a long-standing question due to the lack of high-resolution structure. Here we report the solution NMR structure of the aptamer–OTA complex. It was found that OTA binding induces the aptamer to fold into a well-defined unique duplex–quadruplex structural scaffold stabilized by Mg2+ and Na+ ions. OTA does not directly interact with the G-quadruplex, but specifically binds at the junction between the double helix and G-quadruplex through π–π stacking, halogen bonding (X-bond), and hydrophobic interaction. OTB has the same binding site as OTA but lacks the X-bond. The strong X-bond formed between the chlorine atom of OTA and the aromatic ring of C5 is the key to discriminating the strong binding toward OTA. The present research contributes to a deeper insight of aptamer molecular recognition, reveals structural basis of the high-affinity binding of aptamers, and provides a foundation for further aptamer engineering and applications.

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“…The important interactions between PyPDS and the 3′ binding pocket of MYT1L were also observed by 101 intermolecular nuclear Overhauser effects (NOEs) between PyPDS and MYT1L. Based on NMR restraints, the NMR solution structure of the 1:1 PyPDS–MYT1L complex was calculated. The selected 15 lowest-energy refined structures are displayed in Figure S16.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the structures of the PyPDS–MYT1L and PDS–MYT1L complexes (Figure ), we further analyzed and summarized the structural basis of specific binding between PyPDS/PDS and G4s from the structural characteristics and electronegativity characteristics. In terms of structural characteristics, to improve the selectivity of G4-targeted ligands, ligands need to be designed to match G4-binding sites that are distinct from other nucleic acids as much as possible, thus reducing their affinity for other nucleic acids . The most obvious characteristic of G4 structures from other nucleic acid topologies is that they have large G-tetrad planes.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the reported solution structures of the small molecules and the QDHs, we compared their binding sites. Unlike the binding site of PyPDS/PDS, L 1 Pt(dien) with a large aromatic plane and platinum unit binds to both G-quadruplex and duplex motifs of MYT1L with high spatial matching (Figure a,b), while the aromatic plane stacks at the G-tetrad via π–π stacking and the platinum unit interacts with the duplex region via groove binding. In contrast, the ochratoxin A (OTA) with a small organic plane and flexible scaffold binds to the duplex and other base regions of the OBA33 QDH (Figure c) .…”

Section: Discussionmentioning

confidence: 99%

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Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes

Liu

Zeng

et al. 2022

J. Am. Chem. Soc.

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The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (e.g., PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex–duplex hybrid. The structures indicate that the rigid aromatic rings of PyPDS/PDS linked by flexible amide bonds match adaptively with G-tetrad planes, enhancing π–π stacking and achieving specific recognition of G4s. The aliphatic amine side chains of PyPDS/PDS adjust conformation to interact with the phosphate backbone via hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N–H of PyPDS/PDS amide bonds interacts with two O6s of G-tetrad guanines via hydrogen bonding, achieving a further increase in affinity for G4s, which is different from most G4 ligands. Our findings reveal from structural perspectives that the rational assembly of rigid and flexible structural units in a ligand can synergistically improve the selectivity and affinity for G4s through spatial selective and adaptive matching.

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Spatial Matching Selectivity and Solution Structure of Organic–Metal Hybrid to Quadruplex–Duplex Hybrid

Cited by 19 publications

References 59 publications

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Structural Insights into the Mechanism of High-Affinity Binding of Ochratoxin A by a DNA Aptamer

Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes

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