6H9X

Klebsiella pneumoniae Seryl-tRNA Synthetase in Complex with the Intermediate Analog 5'-O-(N-(L-Seryl)-Sulfamoyl)Adenosine

Summary for 6H9X

• Entry DOI: 10.2210/pdb6h9x/pdb
• Descriptor: Serine--tRNA ligase, 5'-O-(N-(L-SERYL)-SULFAMOYL)ADENOSINE, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: coil-coil, beta barrel, trna synthetase, complex, ligase
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 49409.01

Authors

Pang, L.,De Graef, S.,Strelkov, S.V.,Weeks, S.D. (deposition date: 2018-08-06, release date: 2019-05-15, Last modification date: 2024-01-17)

Primary citation

De Ruysscher, D.,Pang, L.,De Graef, S.,Nautiyal, M.,De Borggraeve, W.M.,Rozenski, J.,Strelkov, S.V.,Weeks, S.D.,Van Aerschot, A.
Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily.
Eur.J.Med.Chem., 174:252-264, 2019

PubMed Abstract: The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS) and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA) compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 Å crystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.

PubMed: 31048140
DOI: 10.1016/j.ejmech.2019.04.045

Experimental method

X-RAY DIFFRACTION (2.1 Å)