2A9Z

Crystal structure of T. gondii adenosine kinase complexed with N6-dimethyladenosine and AMP-PCP

Summary for 2A9Z

• Entry DOI: 10.2210/pdb2a9z/pdb
• Related: 1DGM 1LII 1LIJ 1LIK 1LIO 2A9Y 2AA0 2AB8 2ABS
• Descriptor: adenosine kinase, CHLORIDE ION, SODIUM ION, ... (6 entities in total)
• Functional Keywords: ribokinase fold; alpha/beta; intermediate conformation, signaling protein, transferase
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 1
• Total formula weight: 41761.33

Authors

Zhang, Y.,el Kouni, M.H.,Ealick, S.E. (deposition date: 2005-07-12, release date: 2006-07-11, Last modification date: 2023-08-23)

Primary citation

Zhang, Y.,El Kouni, M.H.,Ealick, S.E.
Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinase
Acta Crystallogr.,Sect.D, 63:126-134, 2007

PubMed Abstract: Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure-activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, the AK-6-methyl mercaptopurine riboside (MMPR) complex and the AK-MMPR-AMP-PCP complex were determined to 1.35, 1.35, 1.75 and 1.75 A resolution, respectively. These structures reveal a conformation intermediate between open and closed, with a small lid-domain rotation of 12 degrees . Residues Gly143-X-X-Gly146 undergo torsional changes upon substrate binding, which together with a Gly68-Gly69 switch induces a hinge bending of the lid domain. The intermediate conformation suggests that ATP binding is independent of adenosine binding. Orienting the gamma-phosphate group of ATP into the optimal catalytic position may be the last step before the onset of chemical catalysis and may require the translocation of Arg136 following the complete closure of the lid domain. 6-Substituted purine-nucleoside analogs are accommodated in a hydrophobic cavity. Modification at the N6 or C6 position of the nucleoside would affect the interactions with the surrounding residues and the binding affinity.

PubMed: 17242506
DOI: 10.1107/S0907444906043654

Experimental method

X-RAY DIFFRACTION (1.35 Å)