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Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Publication ,  Journal Article
Schumacher, MA; Scott, DM; Mathews, II; Ealick, SE; Roos, DS; Ullman, B; Brennan, RG
Published in: J Mol Biol
February 18, 2000

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gi phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.

Duke Scholars

Published In

J Mol Biol

DOI

ISSN

0022-2836

Publication Date

February 18, 2000

Volume

296

Issue

2

Start / End Page

549 / 567

Location

Netherlands

Related Subject Headings

  • Water
  • Tubercidin
  • Toxoplasma
  • Protein Structure, Tertiary
  • Protein Structure, Secondary
  • Prodrugs
  • Molecular Sequence Data
  • Models, Molecular
  • Magnesium
  • Hydrogen Bonding
 

Citation

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ICMJE
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Schumacher, M. A., Scott, D. M., Mathews, I. I., Ealick, S. E., Roos, D. S., Ullman, B., & Brennan, R. G. (2000). Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol, 296(2), 549–567. https://doi.org/10.1006/jmbi.1999.3474
Schumacher, M. A., D. M. Scott, I. I. Mathews, S. E. Ealick, D. S. Roos, B. Ullman, and R. G. Brennan. “Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.J Mol Biol 296, no. 2 (February 18, 2000): 549–67. https://doi.org/10.1006/jmbi.1999.3474.
Schumacher MA, Scott DM, Mathews II, Ealick SE, Roos DS, Ullman B, et al. Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol. 2000 Feb 18;296(2):549–67.
Schumacher, M. A., et al. “Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.J Mol Biol, vol. 296, no. 2, Feb. 2000, pp. 549–67. Pubmed, doi:10.1006/jmbi.1999.3474.
Schumacher MA, Scott DM, Mathews II, Ealick SE, Roos DS, Ullman B, Brennan RG. Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol. 2000 Feb 18;296(2):549–567.
Journal cover image

Published In

J Mol Biol

DOI

ISSN

0022-2836

Publication Date

February 18, 2000

Volume

296

Issue

2

Start / End Page

549 / 567

Location

Netherlands

Related Subject Headings

  • Water
  • Tubercidin
  • Toxoplasma
  • Protein Structure, Tertiary
  • Protein Structure, Secondary
  • Prodrugs
  • Molecular Sequence Data
  • Models, Molecular
  • Magnesium
  • Hydrogen Bonding