A structural dissection of protein–RNA interactions based on different RNA base areas of interfaces

Hu, Wenyuan; Liu, Qin; Li, Menglong; Pu, Xuemei; Guo, Yanzhi

doi:10.1039/c8ra00598b

Cited by 12 publications

(10 citation statements)

References 60 publications

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“…[461][462][463][464] These interactions are not fully understood but typically mediated by (i) H-bonds and van der Waals interactions between proteins (mostly side chains, and mostly by Arg, Lys, Asn and Ser) and the nucleobases (U and G more frequently than A and C), ribose 2'OH, and phosphodiester backbone of RNA (0.5-4.5 kcal/mol per bond), 461,462,[465][466][467] (ii) hydrophobic interactions between RNA bases and hydrophobic side chains (1-2 kcal/mol per interaction), 461,462 (iii)  interactions between nucleobases and aromatic (Trp, His, Phe, and Tyr) or acyclic (Arg, Glu, and Asp) -containing amino acids (2-6 kcal/mol per interaction), with a preference for stacking arrangements, 461,462,468 and (iv) electrostatic attraction between positivelycharged patches on protein surfaces and polyanionic RNA (Figure 16C,D). 462 Compared to DNA, RNA nucleotides are less involved in base-pairing and present an additional ribose 2'-OH, which constitutes additional interaction opportunities. 461,467 RBPs cannot always surround their target the way DNA-binding proteins often do because of the large range of structural elements forming RNA tertiary structures (compare Figure 16 and Figure 14).…”

Section: I-motif Ligandsmentioning

confidence: 99%

Mass Spectrometry of Nucleic Acid Noncovalent Complexes

et al. 2021

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Nucleic acids have been among the first targets for antitumor drugs and antibiotics, and with the unveiling of new biological roles in regulation of gene expression, specific DNA and RNA structures have become very attractive targets, especially when the corresponding proteins are undruggable. Biophysical assays to test target structure and ligand binding stoichiometry, affinity, specificity and binding modes are part of the drug development pipeline. Mass spectrometry offers unique advantages as a biophysical method due to its ability to distinguish each stoichiometry present in a mixture. In addition, advanced mass spectrometry approaches (reactive probing, fragmentation techniques, ion mobility spectrometry, ion spectroscopy) provide more detailed information on the complexes. Here we review the fundamentals of mass spectrometry and all its particularities when studying non-covalent nucleic acid structures, and then review what has been learned thanks to mass spectrometry on nucleic acid structures, self-assemblies (e.g., duplexes or G-quadruplexes), and their complexes with ligands. 47

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Section: I-motif Ligandsmentioning

confidence: 99%

Mass Spectrometry of Nucleic Acid Noncovalent Complexes

et al. 2021

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“…Thus, the strength of the charge–charge interactions between residues may not be accurately described by the electrostatic parameters in our model. Nonetheless, given that the A- and P-site residues are just 4 Å from each other in crystal structures, and that ionic bonding of charged residues with phosphate groups of rRNA can be expected in the tunnel, we propose that counterion screening of these interactions is minimal and therefore large forces could be generated. Unfortunately, as noted, explicit solvent, all-atom simulations do not converge sufficiently to get precise force measurements.…”

Section: Discussionmentioning

confidence: 94%

Ribosome Elongation Kinetics of Consecutively Charged Residues Are Coupled to Electrostatic Force

Leininger

Rodríguez

et al. 2021

Biochemistry

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The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multiscale simulations, that positively charged residues generate large forces that move the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but move the A- and P-sites closer together. These conformational changes, respectively, increase and decrease the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome–nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation and provide a framework for interpreting experimental results on translation speed.

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“…Thus, the strength of the charge-charge interactions between residues may not be accurately described by the electrostatic parameters in our model. Nonetheless, given that the A-and P-site residues are just 4 Å from each other in crystal structures 28 , and that ionic bonding of charged residues with phosphate groups of rRNA can be expected in the tunnel 31 , we propose that counterion screening of these interactions is minimal and therefore large forces could be generated. Unfortunately, as noted, explicit solvent, all-atom simulations do not converge sufficiently to get precise force measurements.…”

Section: Discussionmentioning

confidence: 94%

Ribosome elongation kinetics of consecutively charged residues are coupled to electrostatic force

Leininger

Rodríguez

et al. 2021

Preprint

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The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multi-scale simulations, that positively charged residues generate large forces that pull the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but opposite direction. And that these conformational changes, respectively, raise and lower the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting a proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome-nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation, and provide a framework for interpreting experimental results on translation speed.Abstract FigureFor table of contents use only.

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A structural dissection of protein–RNA interactions based on different RNA base areas of interfaces

Abstract: Qualitative and quantitative measurements of the influence of structure and composition of RNA interfaces on protein–RNA interactions.

Cited by 12 publications

References 60 publications

Mass Spectrometry of Nucleic Acid Noncovalent Complexes

Mass Spectrometry of Nucleic Acid Noncovalent Complexes

Ribosome Elongation Kinetics of Consecutively Charged Residues Are Coupled to Electrostatic Force

Ribosome elongation kinetics of consecutively charged residues are coupled to electrostatic force

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