scholarly journals Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

2021 ◽  
Vol 22 (4) ◽  
pp. 1750
Author(s):  
Luping Pang ◽  
Stephen D. Weeks ◽  
Arthur Van Aerschot
Keyword(s):  
Amino Acid ◽  
Drug Discovery ◽  
Binding Sites ◽  
Resistance Mechanisms ◽  
X Ray ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Inhibitory Mechanisms ◽  
Proof Reading ◽  
Reading Activities

Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.

scholarly journals Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

2019 ◽  
Author(s):  
Ricky Cain ◽  
Ramya Salimraj ◽  
Avinash S. Punekar ◽  
Dom Bellini ◽  
Colin W. G. Fishwick ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Drug Discovery ◽  
Bacterial Species ◽  
Trna Synthetase ◽  
Human Homologue ◽  
X Ray ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Chemical Inhibition ◽  
Selective Chemical

AbstractAminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

scholarly journals The structural basis of the genetic code: amino acid recognition by aminoacyl-tRNA synthetases

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Florian Kaiser ◽  
Sarah Krautwurst ◽  
Sebastian Salentin ◽  
V. Joachim Haupt ◽  
Christoph Leberecht ◽  
...  
Keyword(s):  
Amino Acid ◽  
Genetic Code ◽  
Structural Basis ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Amino Acid Recognition

Modification of aminoacyl-tRNA synthetases with pyridoxal-5′-phosphate. Identification of the labeled amino acid residues

Biochimie ◽  
1994 ◽  
Vol 76 (1) ◽  
pp. 33-44 ◽  
Author(s):  
T. Kalogerakos ◽  
C. Hountondji ◽  
P.F. Berne ◽  
S. Dutka ◽  
S. Blanquet
Keyword(s):  
Amino Acid ◽  
Amino Acid Residues ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases

scholarly journals Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analyses of threonyl-tRNA synthetase editing domain fromAeropyrum pernix

2012 ◽  
Vol 68 (11) ◽  
pp. 1390-1393 ◽  
Author(s):  
Sadeem Ahmad ◽  
Antony S. K. Sravankumar ◽  
Shobha P. Kruparani ◽  
Rajan Sankaranarayanan
Keyword(s):  
Trna Synthetase ◽  
Asymmetric Unit ◽  
Crystallographic Investigation ◽  
X Ray ◽  
Trna Synthetases ◽  
Aeropyrum Pernix ◽  
Substrate Analogues ◽  
Aminoacyl Trna Synthetases ◽  
Editing Domain ◽  
Evolutionary Aspects

The proofreading function of aminoacyl-tRNA synthetases is crucial in maintaining the fidelity of protein synthesis. Most archaeal threonyl-tRNA synthetases (ThrRSs) possess a unique proofreading domain unrelated to their eukaryotic/bacterial counterpart. The crystal structure of this domain from the archaeonPyrococcus abysiiin complex with its cognate and noncognate substrate analogues had given insights into its catalytic and discriminatory mechanisms. To probe further into the mechanistic and evolutionary aspects of this domain, work has been extended to another archaeonAeropyrum pernix. The organism possesses two proteins corresponding to threonyl-tRNA synthetase,i.e.ThrRS1 and ThrRS2, encoded by two different genes,thrS1andthrS2, respectively. ThrRS1 is responsible for aminoacylation and ThrRS2 for proofreading activity. Here the purification, crystallization and preliminary X-ray crystallographic investigation of the N-terminal proofreading domain of ThrRS2 fromA. pernixis reported. The crystals belong to either theP41212 orP43212 space group and consist of one monomer per asymmetric unit.

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