Active Site Nanospace of Aminoacyl tRNA Synthetase: Difference Between the Class I and Class II Synthetases

Dutta, Saheb; Choudhury, Kaberi; Banik, Sindrila Dutta; Nandi, Nilashis

doi:10.1166/jnn.2014.8534

Cited by 14 publications

(18 citation statements)

References 25 publications

(43 reference statements)

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“…Recent studies established that attack by the syn oxygen carboxylic acid group of aa is favorable for class I aaRSs whereas attack by anti oxygen is favorable for class II which is a class specific difference between the reaction mechanism in class I and class II aaRSs 17,19 . SerRS being a class …”

Section: B Dynamics Of the Reaction Centermentioning

confidence: 99%

“…27 Our results corroborate the proposition and present a dynamic view of the same.The observed structural dynamics of the ATP binding subsite leads to the development of interactions of the residues of the subsite and ATP and stabilize the ATP in the bent conformation. The bent conformation of ATP is favored in class II aaRSs over extended conformation for nucleophilic attack19 . The closure of the lid allows the development of hydrogen bonding interaction between loop residues (for example, Glu351 and Arg360) and the ATP.…”

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confidence: 99%

“…As mentioned before, these two states are important conformational states that appear during reaction cycle. To better understand 8 the influence of dimerization, we further studied the dynamics of the active site of monomeric mk SerRS with open active site as well as active site bound with substrates.In the next section we present the computational procedure which is followed by results and discussion.network of interaction of active site residues, the pre-transition state geometry suitable for nucleophilic attack is formed by the reorganization of the active site residues[16][17][18][19][20] . It is mentioned before that the tRNA binds across the dimer surface (a cross-dimer binding)24-26 .…”

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confidence: 99%

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Dynamics of the Active Sites of Dimeric SeryltRNA Synthetase fromMethanopyrus kandleri

Dutta

Nandi

2015

J. Phys. Chem. B

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Aminoacyl tRNA synthetases (aaRSs) carry out the first step of protein biosynthesis. Several aaRSs are multimeric, and coordination between the dynamics of active sites present in each monomer is a prerequisite for the fast and accurate aminoacylation. However, important lacunae of understanding exist concerning the conformational dynamics of multimeric aaRSs. Questions remained unanswered pertaining to the dynamics of the active site. Little is known concerning the conformational dynamics of the active sites in response to the substrate binding, reorganization of the catalytic residues around reactants, time-dependent changes at the reaction center, which are essential for facilitating the nucleophilic attack, and interactions at the interface of neighboring monomers. In the present work, we carried out all-atom molecular dynamics simulation of dimeric (mk)SerRS from Methanopyrus kandleri bound with tRNA using an explicit solvent system. Two dimeric states of seryl tRNA synthetase (open, substrate bound, and adenylate bound) and two monomeric states (open and substrate bound) are simulated with bound tRNA. The aim is to understand the conformational dynamics of (mk)SerRS during its reaction cycle. While the present results provide a clear dynamical perspective of the active sites of (mk)SerRS, they corroborate with the results from the time-averaged experimental data such as crystallographic and mutation analysis of methanogenic SerRS from M. kandleri and M. barkeri. It is observed from the present simulation that the motif 2 loop gates the active site and its Glu351 and Arg360 stabilizes ATP in a bent state favorable for nucleophilic attack. The flexibility of the walls of the active site gradually reduces near reaction center, which is a more organized region compared to the lid region. The motif 2 loop anchors Ser and ATP using Arg349 in a hydrogen bonded geometry crucial for nucleophilic attack and favorably influences the electrostatic potential at the reaction center. Synchronously, Arg366 of the β sheet at the base holds the syn oxygen of the attacking carboxylic group so that the attack by the anti oxygen is feasible. This residue also contributes to the reduction of the unfavorable electrostatic potential at the reaction center. Present simulation clearly shows the catalytic role of the residues at reaction center. A precise and stable geometry of hydrogen bonded network develops within the active site, which is essential for the development of an optimum transition state geometry. All loops move away from the platform of active site in the open or adenylate bound state and the network of hydrogen bond disappears. The serine binding site is most rigid among all three subsites. The Ser is held here in a highly organized geometry bound by Zn(2+) and Cys residues. Present simulation further suggests that the helix-turn-helix motif connecting the monomers might have important role in coordinating the functional dynamics of the two active sites. The N-terminal domain is involved in long-range electrostatic i...

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Section: B Dynamics Of the Reaction Centermentioning

confidence: 99%

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Dynamics of the Active Sites of Dimeric SeryltRNA Synthetase fromMethanopyrus kandleri

Dutta

Nandi

2015

J. Phys. Chem. B

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“…In this case, overall interactions are highly similar but binding geometry and binding site volume is significantly different. Both ligands are attacked from the opposite side 56 as highlighted by significantly different conformations (Fig. 4B).…”

Section: Class Duality Extends Possibilitiesmentioning

confidence: 99%

The Structural Basis of the Genetic Code: Amino Acid Recognition by Aminoacyl-tRNA Synthetases

Kaiser

Krautwurst

Salentin

et al. 2019

Preprint

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Storage and directed transfer of information is the key requirement for the development of life. Yet any information stored on our genes is useless without its correct interpretation. The genetic code defines the rule set to decode this information. Aminoacyl-tRNA synthetases are at the heart of this process. For the first time, we extensively characterize how these enzymes distinguish all natural amino acids based on the computational analysis of crystallographic structure data. The results of this meta-analysis show that the correct read-out of genetic information is a delicate interplay between the composition of the binding site, non-covalent interactions, error correction mechanisms, and steric effects. EvolutionThe evolutionary origin of aaRSs is hard to track. Phylogenetic analyses of aaRS sequences show that they do not follow the standard model of life 14 ; the development of aaRSs was nearly complete before the Last Universal Common Ancestor (LUCA) 15,16 . Their complex evolutionary history included horizontal gene transfer, fusion, duplication, and recombination events 14, 17-21 . Sequence analyses 22 and subsequent structure investigations 23,24 revealed that aaRSs can be divided into two distinct classes (Class I and Class II) that share no similarities at sequence or structure level. Each of the classes is responsible for 10 of the 20 proteinogenic amino acids and can be further grouped into subclasses 15 . Most eukaryotic genomes contain the complete set of 20 aaRSs. However, some species lack certain aaRS-encoding genes and compensate for this by post-modifications 7, 25-27 or alternative pathways [28][29][30] . A scenario where Class I and Class II originated simultaneously from opposite strands of the same gene 31, 32 is among the most popular explanations for the origin of aaRSs. This so-called Rodin-Ohno hypothesis (named after Sergei N. Rodin and Susumu Ohno 31 ) is supported by experimental deconstructions of both aaRS classes [33][34][35] . At the dawn of life the concurrent duality could have allowed to implement an initial binary choice, which is the minimal requirement to establish any code 9 .Biochemical Function In order to fulfill their biological function aaRSs are required to catalyze two distinct reaction steps. Prior to its covalent attachment to the 3' end of the tRNA molecule, the designated amino acid is activated with adenosine triphosphate (ATP) and an aminoacyl-adenylate intermediate is formed 36,37 . In general, the binding sites of aaRSs can be divided into two moieties: the part where ATP is bound as well as the part where specific interactions with the amino acid ligand are established ( Fig. 1). Is is assumed that the amino acid activation with ATP constituted the principal kinetic barrier for the creation of peptides in the prebiotic context 35 . Due to the fundamental importance of this first reaction step, highly conserved sequence 4 and structural motifs 38 exist, which are likely to be vital for the aminoacylation reaction. While the activation of amino acids with ...

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“…The Rodin-Ohno hypothesis is 99 supported by an experimental deconstruction of aaRS sequences [9,11]. In these studies, 100 parts of contemporary aaRS proteins were removed and the catalytic strength of the 101 3/30 resulting transcripts was assessed. One representative sequence of each Class was 102 reduced to a peptide of only 46 amino acids.…”

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Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

Kaiser

Bittrich

Salentin

et al. 2017

Preprint

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The origin of the machinery that realizes protein biosynthesis in all organisms is still unclear. One key component of this machinery are aminoacyl tRNA synthetases (aaRS), which ligate tRNAs to amino acids while consuming ATP. Sequence analyses revealed that these enzymes can be divided into two complementary classes. Both classes differ significantly on a sequence and structural level, feature different reaction mechanisms, and occur in diverse oligomerization states. The one unifying aspect of both classes is their function of binding ATP. We identified Backbone Brackets and Arginine Tweezers as most compact ATP binding motifs characteristic for each Class. Geometric analysis shows a structural rearrangement of the Backbone Brackets upon ATP binding, indicating a general mechanism of all Class I structures. Regarding the origin of aaRS, the Rodin-Ohno hypothesis states that the peculiar nature of the two aaRS classes is the result of their primordial forms, called Protozymes, being encoded on opposite strands of the same gene. Backbone Brackets and Arginine Tweezers were traced back to the proposed Protozymes and their more efficient successors, the Urzymes. Both structural motifs can be observed as pairs of residues in contemporary structures and it seems that the time of their addition, indicated by their placement in the ancient aaRS, coincides with the evolutionary trace of Proto-and Urzymes. Author summaryAminoacyl tRNA synthetases (aaRS) are primordial enzymes essential for interpretation

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Active Site Nanospace of Aminoacyl tRNA Synthetase: Difference Between the Class I and Class II Synthetases

Cited by 14 publications

References 25 publications

Dynamics of the Active Sites of Dimeric SeryltRNA Synthetase fromMethanopyrus kandleri

Dynamics of the Active Sites of Dimeric SeryltRNA Synthetase fromMethanopyrus kandleri

The Structural Basis of the Genetic Code: Amino Acid Recognition by Aminoacyl-tRNA Synthetases

Backbone Brackets and Arginine Tweezers delineate Class I and Class II aminoacyl tRNA synthetases

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