4G5Y
Crystal Structure of Mycobacterium tuberculosis Pantothenate synthetase in a ternary complex with ATP and N,N-DIMETHYLTHIOPHENE-3-SULFONAMIDE
Summary for 4G5Y
| Entry DOI | 10.2210/pdb4g5y/pdb |
| Related | 3COV 3COW 3COY 3COZ 4EF6 4EFK |
| Descriptor | Pantothenate synthetase, ADENOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | drug design, fragment-based, ligase, pantothenate biosynthesis, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 65147.60 |
| Authors | Ciulli, A.,Silvestre, H.L.,Blundell, T.L.,Abell, C. (deposition date: 2012-07-18, release date: 2013-07-03, Last modification date: 2023-09-13) |
| Primary citation | Silvestre, H.L.,Blundell, T.L.,Abell, C.,Ciulli, A. Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery. Proc.Natl.Acad.Sci.USA, 110:12984-12989, 2013 Cited by PubMed Abstract: 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. PubMed: 23872845DOI: 10.1073/pnas.1304045110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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