4A1O

Crystal structure of Mycobacterium tuberculosis PurH complexed with AICAR and a novel nucleotide CFAIR, at 2.48 A resolution.

Summary for 4A1O

• Entry DOI: 10.2210/pdb4a1o/pdb
• Related: 3ZZM
• Descriptor: BIFUNCTIONAL PURINE BIOSYNTHESIS PROTEIN PURH, POTASSIUM ION, AMINOIMIDAZOLE 4-CARBOXAMIDE RIBONUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: transferase-hydrolase
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 111576.64

Authors

Le Nours, J.,Bulloch, E.M.M.,Zhang, Z.,Greenwood, D.R.,Middleditch, M.J.,Dickson, J.M.J.,Baker, E.N. (deposition date: 2011-09-17, release date: 2011-09-28, Last modification date: 2023-12-20)

Primary citation

Le Nours, J.,Bulloch, E.M.M.,Zhang, Z.,Greenwood, D.R.,Middleditch, M.J.,Dickson, J.M.J.,Baker, E.N.
Structural Analyses of a Purine Biosynthetic Enzyme from Mycobacterium Tuberculosis Reveal a Novel Bound Nucleotide.
J.Biol.Chem., 286:40706-, 2011

PubMed Abstract: Enzymes of the de novo purine biosynthetic pathway have been identified as essential for the growth and survival of Mycobacterium tuberculosis and thus have potential for the development of anti-tuberculosis drugs. The final two steps of this pathway are carried out by the bifunctional enzyme 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC), also known as PurH. This enzyme has already been the target of anti-cancer drug development. We have determined the crystal structures of the M. tuberculosis ATIC (Rv0957) both with and without the substrate 5-aminoimidazole-4-carboxamide ribonucleotide, at resolutions of 2.5 and 2.2 Å, respectively. As for other ATIC enzymes, the protein is folded into two domains, the N-terminal domain (residues 1-212) containing the cyclohydrolase active site and the C-terminal domain (residues 222-523) containing the formyltransferase active site. An adventitiously bound nucleotide was found in the cyclohydrolase active site in both structures and was identified by NMR and mass spectral analysis as a novel 5-formyl derivative of an earlier intermediate in the biosynthetic pathway 4-carboxy-5-aminoimidazole ribonucleotide. This result and other studies suggest that this novel nucleotide is a cyclohydrolase inhibitor. The dimer formed by M. tuberculosis ATIC is different from those seen for human and avian ATICs, but it has a similar ∼50-Å separation of the two active sites of the bifunctional enzyme. Evidence in M. tuberculosis ATIC for reactivity of half-the-sites in the cyclohydrolase domains can be attributed to ligand-induced movements that propagate across the dimer interface and may be a common feature of ATIC enzymes.

PubMed: 21956117
DOI: 10.1074/JBC.M111.291138

Experimental method

X-RAY DIFFRACTION (2.48 Å)