4G5Y: Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase in a Ternary Complex With ATP and N,n-dimethylthiophene-3- Sulfonamide

In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hit validation by isothermal titration calorimetry and X-ray crystallography. Our multibiophysical approach identified three distinct binding sites for fragments and laid a solid foundation for successful structure-based elaboration into potent inhibitors.
PDB ID: 4G5YDownload
MMDB ID: 111449
PDB Deposition Date: 2012/7/18
Updated in MMDB: 2013/09 
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4G5Y: dimeric; determined by author and by software (PISA)
Molecular Components in 4G5Y
Label Count Molecule
Proteins (2 molecules)
Pantothenate Synthetase
Molecule annotation
Chemicals (9 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB