Analysis of the π-π Stacking Interactions between the Aminoglycoside Antibiotic Kinase APH(3′)-IIIa and Its Nucleotide Ligands

Boehr, David D.; Farley, Adam R.; Wright, Gerard D.; Cox, James R.

doi:10.1016/s1074-5521(02)00245-4

Cited by 88 publications

(49 citation statements)

References 72 publications

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“…However, the electrostatic potential of heterocyclic adenine and guanine nucleobases of DNA/RNA differ markedly from that of homocyclic conjugated systems such as benzene. Calculations of the electrostatic potential map of adenine illustrates that the negative charge is concentrated on N1, N3, and N7, whereas C8 and N9 have significant positive potential (12). Similar studies on the electrostatic potential of tryptophan suggest a relatively greater negative potential on the six-member ring of the indole side chain than on the five-member heterocycle (13).…”

Section: Resultsmentioning

confidence: 70%

Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin C7

Agarwal

Tikhonov

Metlitskaya

et al. 2012

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

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Several classes of naturally occurring antimicrobials exert their antibiotic activity by specifically targeting aminoacyl-tRNA synthetases, validating these enzymes as drug targets. The aspartyl tRNA synthetase “Trojan horse” inhibitor microcin C7 (McC7) consists of a nonhydrolyzable aspartyl-adenylate conjugated to a hexapeptide carrier that facilitates active import into bacterial cells through an oligopeptide transport system. Subsequent proteolytic processing releases the toxic compound inside the cell. Producing strains of McC7 must protect themselves against autotoxicity that may result from premature processing. The mccF gene confers resistance against endogenous and exogenous McC7 by hydrolyzing the amide bond that connects the peptide and nucleotide moieties of McC7. We present here crystal structures of MccF, in complex with various ligands. The MccF structure is similar to that of dipeptide ld -carboxypeptidase, but with an additional loop proximal to the active site that serves as the primary determinant for recognition of adenylated substrates. Wild-type MccF only hydrolyzes the naturally occurring aspartyl phosphoramidate McC7 and synthetic peptidyl sulfamoyl adenylates that contain anionic side chains. We show that substitutions of two active site MccF residues result in a specificity switch toward aromatic aminoacyl–adenylate substrates. These results suggest how MccF-like enzymes may be used to avert various toxic aminoacyl–adenylates that accumulate during antibiotic biosynthesis or in normal metabolism of the cell.

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Section: Resultsmentioning

confidence: 70%

Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin C7

Agarwal

Tikhonov

Metlitskaya

et al. 2012

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

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“…These data suggest that the proposed hydrophobic cavity is the common binding pocket for agonists and antagonists in TodS. The aromatic side chain of F79 in TodS appears to play a central role in the recognition of a broad series of ligands, and we propose effector recognition to be dominated by pi-pi stacking interactions of effectors and protein residues, a common feature in the molecular recognition of aromatic ligands by proteins (27,28).…”

Section: Discussionmentioning

confidence: 76%

Bacterial sensor kinase TodS interacts with agonistic and antagonistic signals

Büsch

Lacal

Martos

et al. 2007

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

105

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The TodS/TodT two-component system controls expression of the toluene dioxygenase (TOD) pathway for the metabolism of toluene in Pseudomonas putida DOT-T1E. TodS is a sensor kinase that ultimately controls tod gene expression through its cognate response regulator, TodT. We used isothermal titration calorimetry to study the binding of different compounds to TodS and related these findings to their capacity to induce gene expression in vivo. Agonistic compounds bound to TodS and induced gene expression in vivo. Toluene was a powerful agonist, but ortho-substitutions of toluene reduced or abolished in vivo responses, although TodS recognized o-xylene with high affinity. These compounds were called antagonists. We show that agonists and antagonists compete for binding to TodS both in vitro and in vivo. The failure of antagonists to induce gene expression in vivo correlated with their inability to stimulate TodS autophosphorylation in vitro. We propose intramolecular TodS signal transmission, not molecular recognition of compounds by TodS, to be the phenomenon that determines whether a given compound will lead to activation of expression of the tod genes. Molecular modeling identified residues F46, I74, F79, and I114 as being potentially involved in the binding of effector molecules. Alanine substitution mutants of these residues reduced affinities (2-to 345-fold) for both agonistic and antagonistic compounds. Our data indicate that determining the inhibitory activity of antagonists is a potentially fruitful alternative to design specific two-component system inhibitors for the development of new drugs to inhibit processes regulated by two-component systems.histidine kinases ͉ isothermal titration calorimetry ͉ Pseudomonas ͉ two-component systems ͉ aromatic hydrocarbons

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“…K395 stabilizes the complex from the other side via a cation-interaction ( fi g. 4 ). Both interactions contribute with low binding energies of probably -2 to -5 kcal/mol [Boehr et al, 2002;Gallivan and Dougherty, 2000], which corresponds to the low observed K D value of 1.4 m M . The nucleotidebinding mode of KdpBN thus differs from other ATPbinding domains.…”

Section: The Nucleotide-binding Modementioning

confidence: 87%

Prokaryotic Kdp-ATPase: Recent Insights into the Structure and Function of KdpB

et al. 2005

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P-type ATPases are amongst the most abundant enzymes that are responsible for active transport of ions across biological membranes. Within the last 5 years a detailed picture of the structure and function of these transport ATPases has emerged. Here, we report on the recent progress in elucidating the molecular mechanism of a unique, prokaryotic member of P-type ATPases, the Kdp-ATPase. The review focuses on the catalytic parts of the central subunit, KdpB. The structure of the nucleotide-binding domain was solved by NMR spectroscopy at high resolution and a model of the nucleotide-binding mode was presented. The nucleotide turned out to be ‘clipped’ into the binding pocket by a π-π interaction to F377 on one side and a cation-π interaction to K395 on the other. The ³⁹⁵KGXXD/E motif and thus the nucleotide-binding mode seems to be conserved in all P-type ATPases, except the heavy metal-transporting (class IB) ATPases. Hence, it can be concluded that KdpB is currently misgrouped as class IA. Mutational studies on two highly conserved residues (D583 and K586) in the transmembrane helix 5 of KdpB revealed that they are indispensable in coupling ATP hydrolysis to ion translocation. Based on these results, two possible pathways for the reaction cycle are discussed.

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Analysis of the π-π Stacking Interactions between the Aminoglycoside Antibiotic Kinase APH(3′)-IIIa and Its Nucleotide Ligands

Cited by 88 publications

References 72 publications

Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin C7

Structure and function of a serine carboxypeptidase adapted for degradation of the protein synthesis antibiotic microcin C7

Bacterial sensor kinase TodS interacts with agonistic and antagonistic signals

Prokaryotic Kdp-ATPase: Recent Insights into the Structure and Function of KdpB

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