3IOE

Crystal Structure of Mycobacterium Tuberculosis Pantothenate Synthetase at 1.95 Ang resolution in complex with 5'-deoxy-5'-((R)-3,4-dihydroxybutylthio)-adenosine

Summary for 3IOE

• Entry DOI: 10.2210/pdb3ioe/pdb
• Related: 1N2H 3COV 3COW 3IOB 3IOC 3IOD
• Descriptor: Pantothenate synthetase, 5'-S-[(3R)-3,4-dihydroxybutyl]-5'-thioadenosine, GLYCEROL, ... (6 entities in total)
• Functional Keywords: mycobacterium tuberculosis, pantothenate biosynthesis, enzymes, ligase, inhibitors, drug design, fragment-based, dynamic combinatorial chemistry, atp-binding, magnesium, metal-binding, nucleotide-binding
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 64353.63

Authors

Ciulli, A.,Scott, D.E.,Abell, C. (deposition date: 2009-08-14, release date: 2009-12-01, Last modification date: 2023-09-06)

Primary citation

Scott, D.E.,Dawes, G.J.,Ando, M.,Abell, C.,Ciulli, A.
A Fragment-Based Approach to Probing Adenosine Recognition Sites by Using Dynamic Combinatorial Chemistry
Chembiochem, 10:2772-2779, 2009

PubMed Abstract: A new strategy that combines the concepts of fragment-based drug design and dynamic combinatorial chemistry (DCC) for targeting adenosine recognition sites on enzymes is reported. We demonstrate the use of 5'-deoxy-5'-thioadenosine as a noncovalent anchor fragment in dynamic combinatorial libraries templated by Mycobacterium tuberculosis pantothenate synthetase. A benzyl disulfide derivative was identified upon library analysis by HPLC. Structural and binding studies of protein-ligand complexes by X-ray crystallography and isothermal titration calorimetry informed the subsequent optimisation of the DCC hit into a disulfide containing the novel meta-nitrobenzyl fragment that targets the pantoate binding site of pantothenate synthetase. Given the prevalence of adenosine-recognition motifs in enzymes, our results provide a proof-of-concept for using this strategy to probe adjacent pockets for a range of adenosine binding enzymes, including other related adenylate-forming ligases, kinases, and ATPases, as well as NAD(P)(H), CoA and FAD(H2) binding proteins.

PubMed: 19827080
DOI: 10.1002/cbic.200900537

Experimental method

X-RAY DIFFRACTION (1.95 Å)