6H9X

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Acylated sulfonamide adenosines as potent inhibitors of the adenylate-forming enzyme superfamily.

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.

(2019) Eur J Med Chem 174: 252-264

  • DOI: https://doi.org/10.1016/j.ejmech.2019.04.045
  • Primary Citation of Related Structures:  
    6H9X

  • 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.


  • Organizational Affiliation

    KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 BOX 1030, 3000 Leuven, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine--tRNA ligase430Klebsiella pneumoniaeMutation(s): 0 
Gene Names: 
EC: 6.1.1.11
UniProt
Find proteins for W9BNU9 (Klebsiella pneumoniae)
Explore W9BNU9 
Go to UniProtKB:  W9BNU9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupW9BNU9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SSA BindingDB:  6H9X Ki: 0.18 (nM) from 1 assay(s)
Kd: 1.3 (nM) from 1 assay(s)
IC50: 210 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.407α = 90
b = 84.407β = 90
c = 229.874γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACTdata extraction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Research Foundation - FlandersBelgiumG077814N
Research Foundation - FlandersBelgiumG0A4616N
Research Foundation - FlandersBelgium1109117N

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-15
    Type: Initial release
  • Version 1.1: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description