6QX1

2.7A structure of benzoisoxazole 3 with S.aureus DNA gyrase and DNA.

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase.

Thalji, R.K., Raha, K., Andreotti, D., Checchia, A., Cui, H., Meneghelli, G., Profeta, R., Tonelli, F., Tommasi, S., Bakshi, T., Donovan, B.T., Howells, A., Jain, S., Nixon, C., Quinque, G., McCloskey, L., Bax, B.D., Neu, M., Chan, P.F., Stavenger, R.A.

(2019) Bioorg Med Chem Lett 29: 1407-1412

  • DOI: https://doi.org/10.1016/j.bmcl.2019.03.029
  • Primary Citation of Related Structures:  
    6QX1, 6QX2

  • PubMed Abstract: 

    A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

    • Organizational Affiliation: 

    GlaxoSmithKline, Collegeville, PA 19426, USA.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
DNA gyrase subunit BA [auth B],
C [auth D]		202Staphylococcus aureusMutation(s): 0 
Gene Names: gyrB, SA0005
EC: 5.99.1.3 (PDB Primary Data), 5.6.2.2 (UniProt)
UniProt
Find proteins for P0A0K8 (Staphylococcus aureus)
Explore P0A0K8 
Go to UniProtKB:  P0A0K8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0A0K8
Sequence Annotations
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  • Reference Sequence
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(by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
DNA gyrase subunit AB [auth A],
D [auth C]		490Staphylococcus aureusMutation(s): 0 
Gene Names: gyrA, SA0006
EC: 5.99.1.3 (PDB Primary Data), 5.6.2.2 (UniProt)
UniProt
Find proteins for Q99XG5 (Staphylococcus aureus (strain N315))
Explore Q99XG5 
Go to UniProtKB:  Q99XG5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99XG5
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains LengthOrganismImage
DNA (5'-D(*AP*GP*CP*CP*GP*TP*AP*GP*GP*TP*AP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3')
E, F
20synthetic construct
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JK8 (Subject of Investigation/LOI)
Query on JK8
Download Ideal Coordinates CCD File 
H [auth B],
L [auth D]		(2~{R})-2-[[5-(2-chlorophenyl)-1,2-benzoxazol-3-yl]oxy]-2-phenyl-ethanamine
C21 H17 Cl N2 O2
HHSLFPVGKCXEOG-FQEVSTJZSA-N
GOL
Query on GOL
Download Ideal Coordinates CCD File 
I [auth A],
J [auth A],
O [auth C],
P [auth E],
Q [auth E]		GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
GLY
Query on GLY
Download Ideal Coordinates CCD File 
M [auth C]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-UHFFFAOYSA-N
MN
Query on MN
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G [auth B],
K [auth D]		MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CL
Query on CL
Download Ideal Coordinates CCD File 
N [auth C]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.206 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.164 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.19α = 90
b = 93.19β = 90
c = 408.99γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
SCALAdata scaling
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

  • Released Date: 2019-04-17 
    • Deposition Author(s): Bax, B.D.
Funding OrganizationLocationGrant Number
European Union115583

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-17
    Type: Initial release
  • Version 1.1: 2019-05-08
    Changes: Data collection, Database references
  • Version 1.2: 2019-07-10
    Changes: Data collection
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description