4DDK

Pantothenate synthetase in complex with 1,3-benzodioxole-5-carboxylic acid

Summary for 4DDK

• Entry DOI: 10.2210/pdb4ddk/pdb
• Related: 4DDH 4DDM
• Descriptor: Pantothenate synthetase, 1,3-benzodioxole-5-carboxylic acid, GLYCEROL, ... (6 entities in total)
• Functional Keywords: fragment-based drug discovery, alpha beta/adenine nucleotide alpha hydrolase-like, pantoate and b-ala binding, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cytoplasm (Potential): P0A5R0
• Total number of polymer chains: 2
• Total formula weight: 64163.33

Authors

Silvestre, H.L. (deposition date: 2012-01-18, release date: 2013-02-13, 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

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: 23872845
DOI: 10.1073/pnas.1304045110

Experimental method

X-RAY DIFFRACTION (1.75 Å)