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1N2B

Crystal Structure of a Pantothenate Synthetase from M. tuberculosis in complex with AMPCPP and pantoate, higher occupancy of pantoate and lower occupancy of AMPCPP in subunit A

Summary for 1N2B
Entry DOI10.2210/pdb1n2b/pdb
Related1MOP 1N2E 1N2G 1N2H 1N2I 1N2J 1N2O
DescriptorPantothenate synthetase, MAGNESIUM ION, SULFATE ION, ... (8 entities in total)
Functional Keywordsrossmann fold, dimer, intersubunit beta sheet, structural genomics, psi, protein structure initiative, tb structural genomics consortium, tbsgc, ligase
Biological sourceMycobacterium tuberculosis
Cellular locationCytoplasm (Potential): P0A5R0
Total number of polymer chains2
Total formula weight64809.06
Authors
Wang, S.,Eisenberg, D.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2002-10-22, release date: 2003-04-22, Last modification date: 2024-02-14)
Primary citationWang, S.,Eisenberg, D.
Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate
Protein Sci., 12:1097-1108, 2003
Cited by
PubMed Abstract: Pantothenate biosynthesis is essential for the virulence of Mycobacterium tuberculosis, and this pathway thus presents potential drug targets against tuberculosis. We determined the crystal structure of pantothenate synthetase (PS) from M. tuberculosis, and its complexes with AMPCPP, pantoate, and a reaction intermediate, pantoyl adenylate, with resolutions from 1.6 to 2 A. PS catalyzes the ATP-dependent condensation of pantoate and beta-alanine to form pantothenate. Its structure reveals a dimer, and each subunit has two domains with tight association between domains. The active-site cavity is on the N-terminal domain, partially covered by the C-terminal domain. One wall of the active site cavity is flexible, which allows the bulky AMPCPP to diffuse into the active site to nearly full occupancy when crystals are soaked in solutions containing AMPCPP. Crystal structures of the complexes with AMPCPP and pantoate indicate that the enzyme binds ATP and pantoate tightly in the active site, and brings the carboxyl oxygen of pantoate near the alpha-phosphorus atom of ATP for an in-line nucleophilic attack. When crystals were soaked with, or grown in the presence of, both ATP and pantoate, a reaction intermediate, pantoyl adenylate, is found in the active site. The flexible wall of the active site cavity becomes ordered when the intermediate is in the active site, thus protecting it from being hydrolyzed. Binding of beta-alanine can occur only after pantoyl adenylate is formed inside the active site cavity. The tight binding of the intermediate pantoyl adenylate suggests that nonreactive analogs of pantoyl adenylate may be inhibitors of the PS enzyme with high affinity and specificity.
PubMed: 12717031
DOI: 10.1110/ps.0241803
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.7 Å)
Structure validation

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