Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance

Anjana, Ramnath; Vaishnavi, Marthandan Kirti; Sherlin, Durairaj; Kumar, Surapaneni Pavan; Naveen, Kora; Kanth, Pasam Sandeep; Sekar, K.

doi:10.6026/97320630081220

Cited by 86 publications

(80 citation statements)

References 14 publications

(24 reference statements)

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“…4d–j) resulting in differences in van der Waals (>4 Å), aromatic (4.5–7 Å) 39 , and ionic (~4 Å) 40 interactions. We caution that due to the modest resolution, the accuracy of these measurement will contain some degree of error.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Coleman

Gouaux

2018

Nat Struct Mol Biol

130

136

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Section: Discussionmentioning

confidence: 99%

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Coleman

Gouaux

2018

Nat Struct Mol Biol

130

136

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“…Phenylalanine (Phe), Tyrosine (Tyr), Histidine (His) and Tryptophan (Trp); the six-membered carbon ring from both Phe and Tyr, five-membered ring in the indole group from Trp and imidazole group from His were used to calculate the ring centroids and plane angles. The residue pairs within a ring centroid distance of 4.5–7.0 Å (min-max) were considered in each frame for both the trajectories58. Further, for these residues normal vectors were calculated to identify the angle (θ) between the two planes.…”

Section: Methodsmentioning

confidence: 99%

Comparative molecular dynamics studies of heterozygous open reading frames of DNA polymerase eta (η) in pathogenic yeast Candida albicans

Satpati

Manohar

Acharya

et al. 2017

Sci Rep

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Genomic instability in Candida albicans is believed to play a crucial role in fungal pathogenesis. DNA polymerases contribute significantly to stability of any genome. Although Candida Genome database predicts presence of S. cerevisiae DNA polymerase orthologs; functional and structural characterizations of Candida DNA polymerases are still unexplored. DNA polymerase eta (Polη) is unique as it promotes efficient bypass of cyclobutane pyrimidine dimers. Interestingly, C. albicans is heterozygous in carrying two Polη genes and the nucleotide substitutions were found only in the ORFs. As allelic differences often result in functional differences of the encoded proteins, comparative analyses of structural models and molecular dynamic simulations were performed to characterize these orthologs of DNA Polη. Overall structures of both the ORFs remain conserved except subtle differences in the palm and PAD domains. The complementation analysis showed that both the ORFs equally suppressed UV sensitivity of yeast rad30 deletion strain. Our study has predicted two novel molecular interactions, a highly conserved molecular tetrad of salt bridges and a series of π–π interactions spanning from thumb to PAD. This study suggests these ORFs as the homologues of yeast Polη, and due to its heterogeneity in C. albicans they may play a significant role in pathogenicity.

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“…5d-f, Fig. 6) resulting in differences in van der Waals (>4 Å), aromatic (4.5-7 Å) 37 , and ionic (~4 Å) 38 interactions. In subsite A, the distance …”

Section: Cc-by-nc-nd 40 International License Peer-reviewed) Is the mentioning

confidence: 99%

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Coleman

Gouaux

2017

Preprint

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Selective serotonin reuptake inhibitors are clinically prescribed antidepressants that act by increasing the local concentration of neurotransmitter at synapses and in extracellular spaces via blockade of the serotonin transporter. Here we report x-ray structures of engineered thermostable variants of the human serotonin transporter bound to the antidepressants sertraline, fluvoxamine, and paroxetine. The drugs prevent serotonin binding by occupying the central substrate binding site and stabilizing the transporter in an outward-open conformation.These structures explain how residues within the central site orchestrate binding of chemically diverse inhibitors and mediate transporter-drug selectivity. MAIN TEXTIn the central nervous system the serotonin transporter (SERT) modulates serotoninergic signaling by carrying out the uptake of serotonin (5-HT) from the synaptic space into presynaptic . An extracellular vestibule in the outward-facing conformation 7,9,10 forms a secondary, allosteric site which, when occupied by ligands, can result . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/204859 doi: bioRxiv preprint first posted online Oct. 17, 2017; page 3 of 15 in modulation of transporter activity by altering the kinetics of ligand dissociation from the central site [11][12][13] . Addictive substances such as cocaine and amphetamine bind to monoamine transporters and can either inhibit NT transport or promote NT efflux, respectively 14,15 . Selective serotonin reuptake inhibitors (SSRIs) are a class of small molecules that are highly selective for SERT over DAT and NET and that inhibit 5-HT reuptake with nanomolar potency Fig. 1), and as a consequence these compounds bind with a range of affinities to SERT. Sertraline contains a tetrahydronaphthalene ring system linked to a secondary amine together with a meta and para substituted dichlorophenyl group. Fluvoxamine, by contrast, consists of a 2-aminoethyloxime moiety attached to a methyoxybutyl group, and a phenyl group containing a trifluoronated methyl at the para positon. Fluoxetine also contains a trifluoronated aromatic group but is instead coupled to a phenylpropylamine moiety. Paroxetine and citalopram also differ substantially in the structures of their aromatic, amine, and halogenated substitutents.Recently, we solved x-ray structures of a thermostabilized, transport-inactive construct of human SERT, deemed the ts3 construct, in complex with the SSRIs paroxetine and citalopram 8 .We employed the thermostabilized variant of SERT in order to facilitate purification and crystallization 19,20 . One of the thermostabilizing mutations, however, involves a residue (Thr439Ser) that is directly positioned within the central binding site, in close proximity to the bound SSRIs. Moreover, recent computational modeling of a wild-type SERT-paroxetine complex, in which the structure of the Drosophila DAT was used as a ...

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Aromatic-aromatic interactions in structures of proteins and protein-DNA complexes: a study based on orientation and distance

Cited by 86 publications

References 14 publications

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

Comparative molecular dynamics studies of heterozygous open reading frames of DNA polymerase eta (η) in pathogenic yeast Candida albicans

Structural basis for recognition of diverse antidepressants by the human serotonin transporter

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