PDBsum entry 1lio

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protein links
Transferase PDB id
Protein chain
329 a.a. *
Waters ×179
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of apo t. Gondii adenosine kinase
Structure: Adenosine kinase. Chain: a. Synonym: ak, adenosine 5'-phosphotransferase. Engineered: yes
Source: Toxoplasma gondii. Organism_taxid: 5811. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.50Å     R-factor:   0.200     R-free:   0.260
Authors: M.A.Schumacher,D.M.Scott,I.I.Mathews,S.E.Ealick,R.G.Brennan
Key ref:
M.A.Schumacher et al. (2000). Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol, 298, 875-893. PubMed id: 10801355 DOI: 10.1006/jmbi.2000.3753
17-Apr-02     Release date:   12-Jun-02    
Supersedes: 1dh2
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q9TVW2  (ADK_TOXGO) -  Adenosine kinase
363 a.a.
329 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Adenosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + adenosine = ADP + AMP
+ adenosine
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     AMP salvage   3 terms 
  Biochemical function     nucleotide binding     7 terms  


DOI no: 10.1006/jmbi.2000.3753 J Mol Biol 298:875-893 (2000)
PubMed id: 10801355  
Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.
M.A.Schumacher, D.M.Scott, I.I.Mathews, S.E.Ealick, D.S.Roos, B.Ullman, R.G.Brennan.
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 gamma 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.
  Selected figure(s)  
Figure 3.
Figure 3. AK-substrate contacts. (a) View of the adenosine binding pocket of the AK:adenosine:AMP-PCP complex. Side-chain and adenosine atoms are in blue for nitrogen atoms, red for oxygen atoms and white for carbon atoms. Water molecules, the names of which are abbreviated, e.g. Wat1 is W1, are indicated by red spheres. Hydrogen bonds are represented by broken lines with distances shown in Å. (b) View of the ATP (AMP-PCP) binding pocket of the AK:adenosine:AMP-PCP complex. The atoms and water molecules are as in (a) with phosphorous atoms, orange. Note the absence of specific protein contacts to the AMP-PCP adenine moiety. For clarity sake, several contacts are not shown in both figures.
Figure 4.
Figure 4. Comparison of T. gondii and human AK substrate binding sites. (a) Comparison of the adenosine binding site. The figure was generated after superposition of the structures of the T. gondii AK:adenosine:AMP-PCP (red) and the human AK:adenosine (green) complexes. The Figure emphasizes the near-identical adenosine binding mechanisms of the two enzymes and striking conservation of W1 (Wat1) and W2 (Wat2), the former of which discriminates against 6-oxopurines. (b) Comparison of the ATP binding site. The Figure was generated and is colored as described in (a). This superposition reveals the non-conserved nature of the ATP contacts of these enzymes, particularly to the adenine moiety. For example, the side-chain of Gln346 in the T. gondii enzyme contacts the adenine moiety while that of the corresponding residue in the human AK, Ser328, points out of the pocket.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 298, 875-893) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19548321 V.Guixé, and F.Merino (2009).
The ADP-dependent sugar kinase family: kinetic and evolutionary aspects.
  IUBMB Life, 61, 753-761.  
18625008 F.Merino, and V.Guixé (2008).
Specificity evolution of the ADP-dependent sugar kinase family: in silico studies of the glucokinase/phosphofructokinase bifunctional enzyme from Methanocaldococcus jannaschii.
  FEBS J, 275, 4033-4044.  
19021762 H.Ota, S.Sakasegawa, Y.Yasuda, S.Imamura, and T.Tamura (2008).
A novel nucleoside kinase from Burkholderia thailandensis.
  FEBS J, 275, 5865-5872.  
18329005 M.C.Long, S.C.Shaddix, O.Moukha-Chafiq, J.A.Maddry, L.Nagy, and W.B.Parker (2008).
Structure-activity relationship for adenosine kinase from Mycobacterium tuberculosis II. Modifications to the ribofuranosyl moiety.
  Biochem Pharmacol, 75, 1588-1600.  
17698621 A.Lüscher, P.Onal, A.M.Schweingruber, and P.Mäser (2007).
Adenosine kinase of Trypanosoma brucei and its role in susceptibility to adenosine antimetabolites.
  Antimicrob Agents Chemother, 51, 3895-3901.  
17766369 F.N.Musayev, M.L.di Salvo, T.P.Ko, A.K.Gandhi, A.Goswami, V.Schirch, and M.K.Safo (2007).
Crystal Structure of human pyridoxal kinase: structural basis of M(+) and M(2+) activation.
  Protein Sci, 16, 2184-2194.
PDB codes: 2yxt 2yxu
17021658 T.Hansen, L.Arnfors, R.Ladenstein, and P.Schönheit (2007).
The phosphofructokinase-B (MJ0406) from Methanocaldococcus jannaschii represents a nucleoside kinase with a broad substrate specificity.
  Extremophiles, 11, 105-114.  
17306769 Y.A.Kim, A.Sharon, C.K.Chu, R.H.Rais, O.N.Al Safarjalani, F.N.Naguib, and M.H.el Kouni (2007).
Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents.
  Biochem Pharmacol, 73, 1558-1572.  
16444581 J.Park, B.Singh, and R.S.Gupta (2006).
Inhibition of adenosine kinase by phosphonate and bisphosphonate derivatives.
  Mol Cell Biochem, 283, 11-21.  
16929110 L.Arnfors, T.Hansen, P.Schönheit, R.Ladenstein, and W.Meining (2006).
Structure of Methanocaldococcus jannaschii nucleoside kinase: an archaeal member of the ribokinase family.
  Acta Crystallogr D Biol Crystallogr, 62, 1085-1097.
PDB codes: 2c49 2c4e
16740960 M.K.Safo, F.N.Musayev, M.L.di Salvo, S.Hunt, J.B.Claude, and V.Schirch (2006).
Crystal structure of pyridoxal kinase from the Escherichia coli pdxK gene: implications for the classification of pyridoxal kinases.
  J Bacteriol, 188, 4542-4552.
PDB codes: 2ddm 2ddo 2ddw
15590634 C.Wrenger, M.L.Eschbach, I.B.Müller, D.Warnecke, and R.D.Walter (2005).
Analysis of the vitamin B6 biosynthesis pathway in the human malaria parasite Plasmodium falciparum.
  J Biol Chem, 280, 5242-5248.  
16030223 F.McArthur, C.E.Andersson, S.Loutet, S.L.Mowbray, and M.A.Valvano (2005).
Functional analysis of the glycero-manno-heptose 7-phosphate kinase domain from the bifunctional HldE protein, which is involved in ADP-L-glycero-D-manno-heptose biosynthesis.
  J Bacteriol, 187, 5292-5300.  
  16511104 L.Arnfors, T.Hansen, W.Meining, P.Schönheit, and R.Ladenstein (2005).
Expression, purification, crystallization and preliminary X-ray analysis of a nucleoside kinase from the hyperthermophile Methanocaldococcus jannaschii.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 591-594.  
  16511094 Y.Wang, M.C.Long, S.Ranganathan, V.Escuyer, W.B.Parker, and R.Li (2005).
Overexpression, purification and crystallographic analysis of a unique adenosine kinase from Mycobacterium tuberculosis.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 553-557.  
14722069 M.H.Li, F.Kwok, W.R.Chang, S.Q.Liu, S.C.Lo, J.P.Zhang, T.Jiang, and D.C.Liang (2004).
Conformational changes in the reaction of pyridoxal kinase.
  J Biol Chem, 279, 17459-17465.
PDB codes: 1rft 1rfu 1rfv
15130468 N.N.Suzuki, K.Koizumi, M.Fukushima, A.Matsuda, and F.Inagaki (2004).
Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.
  Structure, 12, 751-764.
PDB codes: 1udw 1uei 1uej 1ufq 1uj2
14609716 A.R.Van Rompay, M.Johansson, and A.Karlsson (2003).
Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases.
  Pharmacol Ther, 100, 119-139.  
12906824 N.Manoj, E.Strauss, T.P.Begley, and S.E.Ealick (2003).
Structure of human phosphopantothenoylcysteine synthetase at 2.3 A resolution.
  Structure, 11, 927-936.
PDB code: 1p9o
12244046 A.Chakraborty, I.Das, R.Datta, B.Sen, D.Bhattacharyya, C.Mandal, and A.K.Datta (2002).
A single-domain cyclophilin from Leishmania donovani reactivates soluble aggregates of adenosine kinase by isomerase-independent chaperone function.
  J Biol Chem, 277, 47451-47460.  
12237466 H.Tsuge, H.Sakuraba, T.Kobe, A.Kujime, N.Katunuma, and T.Ohshima (2002).
Crystal structure of the ADP-dependent glucokinase from Pyrococcus horikoshii at 2.0-A resolution: a large conformational change in ADP-dependent glucokinase.
  Protein Sci, 11, 2456-2463.
PDB code: 1l2l
12235162 M.H.Li, F.Kwok, W.R.Chang, C.K.Lau, J.P.Zhang, S.C.Lo, T.Jiang, and D.C.Liang (2002).
Crystal structure of brain pyridoxal kinase, a novel member of the ribokinase superfamily.
  J Biol Chem, 277, 46385-46390.
PDB codes: 1lhp 1lhr
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.