CH−π “T-Shape” Interaction with Histidine Explains Binding of Aromatic Galactosides to <i>Pseudomonas aeruginosa</i> Lectin LecA

Kadam, Rameshwar U.; Garg, Divita; Schwartz, J.; Visini, Ricardo; Sattler, Michael; Stocker, Achim; Darbre, Tamis; Reymond, Jean‐Louis

doi:10.1021/cb400303w

Cited by 95 publications

(130 citation statements)

References 32 publications

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“…Kadam et al argued that this 4:1 prevalence of HisCH···π over HisNH···π interactions "suggest a more stable arrangement in (the) condensed phase contrasting with the more stable NH···π interactions reported for gas-phase computations". 10 Our results agree with the datamining study inasmuch as the optimum imidazole·benzene interaction is T shaped. However, and in agreement with previous theoretical studies, 11,22 the optimum interaction is NH···π, with no evidence for a CH···π interaction.…”

Section: Discussionsupporting

confidence: 91%

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

et al. 2015

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NH···π hydrogen bonds occur frequently between the amino acid side groups in proteins and peptides. Data-mining studies of protein crystals find that ∼80% of the T-shaped histidine···aromatic contacts are CH···π, and only ∼20% are NH···π interactions. We investigated the infrared (IR) and ultraviolet (UV) spectra of the supersonic-jet-cooled imidazole·benzene (Im·Bz) complex as a model for the NH···π interaction between histidine and phenylalanine. Ground- and excited-state dispersion-corrected density functional calculations and correlated methods (SCS-MP2 and SCS-CC2) predict that Im·Bz has a Cs-symmetric T-shaped minimum-energy structure with an NH···π hydrogen bond to the Bz ring; the NH bond is tilted 12° away from the Bz C6 axis. IR depletion spectra support the T-shaped geometry: The NH stretch vibrational fundamental is red shifted by -73 cm(-1) relative to that of bare imidazole at 3518 cm(-1), indicating a moderately strong NH···π interaction. While the S0(A1g) → S1(B2u) origin of benzene at 38 086 cm(–1) is forbidden in the gas phase, Im·Bz exhibits a moderately intense S0 → S1 origin, which appears via the D(6h) → Cs symmetry lowering of Bz by its interaction with imidazole. The NH···π ground-state hydrogen bond is strong, De=22.7 kJ/mol (1899 cm–1). The combination of gas-phase UV and IR spectra confirms the theoretical predictions that the optimum Im·Bz geometry is T shaped and NH···π hydrogen bonded. We find no experimental evidence for a CH···π hydrogen-bonded ground-state isomer of Im·Bz. The optimum NH···π geometry of the Im·Bz complex is very different from the majority of the histidine·aromatic contact geometries found in protein database analyses, implying that the CH···π contacts observed in these searches do not arise from favorable binding interactions but merely from protein side-chain folding and crystal-packing constraints. The UV and IR spectra of the imidazole·(benzene)2 cluster are observed via fragmentation into the Im·Bz+ mass channel. The spectra of Im·Bz and Im·Bz2 are cleanly separable by IR hole burning. The UV spectrum of Im·Bz2 exhibits two 000 bands corresponding to the S0 → S1 excitations of the two inequivalent benzenes, which are symmetrically shifted by -86/+88 cm(-1) relative to the 000 band of benzene

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Section: Discussionsupporting

confidence: 91%

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

et al. 2015

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“…3 E and F). Such unconventional H-bonds can contribute ∼1 Kcal/mol to the binding energy (26)(27)(28). Further, the carbonyl of the ethylacetate moiety forms an intramolecular H-bond with the Arbidol dimethylamine group that constrains the Arbidol conformation so that the ethylacetate moiety is directed toward the hydrophobic patch containing Pro293 and Phe294 and stabilizes the CH-π interactions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Kadam

Wilson

2016

Proc. Natl. Acad. Sci. U.S.A.

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365

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The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ∼16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter-and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.influenza virus | hemagglutinin | X-ray crystallography | Arbidol | fusion inhibitor

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“…[23] The strong stabilization in the case of G2 is due to the presence of the phenyl aglycon, which is able to participate in a p-CH interaction with the His50 of LecA. [29,53] Although the phenyl group drastically enhances the binding of galactoclusters with LecA,t he presence of the galactose is still essential. With tetravalent phenylbearing molecules (no galactose residues but with the phenyl groups), no interactions are observed (see the Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

Effects of the Surface Densities of Glycoclusters on the Determination of Their IC₅₀ and K_d Value Determination by Using a Microarray

et al. 2015

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Pseudomonas aeruginosa (PA) is an opportunistic bacterium involved in 10-30% of nosocomial diseases. It causes severe lung injury to cystic fibrosis patients, often leading to patient death. PA strains are multidrug resistant, thus making the design of new therapeutics a challenge for public health. One promising therapeutic option is to design glycoclusters that target the virulence factor of PA. LecA is a galactose-specific lectin that might be involved in adhesion and biofilm formation by PA. The DNA-directed immobilization (DDI) microarray is a powerful tool for screening and understanding of structure-activity relationships between glycoclusters and lectins. High-throughput and multiplexed analysis of lectin-glycocluster interactions on a DDI microarray allows measurement of IC50 and dissociation constant (Kd ) values with minute amounts of material. In order to study the robustness of the DDI microarray in determination of IC50 and Kd values, the impact of glycocluster surface density was investigated. The data obtained show that measured IC50 values were influenced by glycocluster surface density: as the density of glycoclusters increases, the measured IC50 values increase too. In contrast, the measured Kd values were not affected by glycocluster surface density, provided that the experimental conditions allow interaction between glycocluster and lectin at single-molecule level (no surface cluster effect).

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CH−π “T-Shape” Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa Lectin LecA

Cited by 95 publications

References 32 publications

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Effects of the Surface Densities of Glycoclusters on the Determination of Their IC₅₀ and K_d Value Determination by Using a Microarray

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CH−π “T-Shape” Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa Lectin LecA

Cited by 95 publications

References 32 publications

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

Modeling the Histidine–Phenylalanine Interaction: The NH···π Hydrogen Bond of Imidazole·Benzene

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Effects of the Surface Densities of Glycoclusters on the Determination of Their IC50 and Kd Value Determination by Using a Microarray

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Product

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Effects of the Surface Densities of Glycoclusters on the Determination of Their IC₅₀ and K_d Value Determination by Using a Microarray