4ACS
Crystal structure of mutant GST A2-2 with enhanced catalytic efficiency with azathioprine
Summary for 4ACS
| Entry DOI | 10.2210/pdb4acs/pdb |
| Related | 1AGS 2VCT 2WJU |
| Descriptor | GLUTATHIONE S-TRANSFERASE A2, GLUTATHIONE (3 entities in total) |
| Functional Keywords | transferase, oxidation-reduction |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 4 |
| Total formula weight | 103740.24 |
| Authors | Zhang, W.,Moden, O.,Tars, K.,Mannervik, B. (deposition date: 2011-12-19, release date: 2011-12-28, Last modification date: 2023-12-20) |
| Primary citation | Zhang, W.,Moden, O.,Tars, K.,Mannervik, B. Structure-based redesign of GST A2-2 for enhanced catalytic efficiency with azathioprine. Chem.Biol., 19:414-421, 2012 Cited by PubMed Abstract: Glutathione transferase (GST) A2-2 is the most efficient human enzyme in the biotransformation of the prodrug azathioprine (Aza). The activation of Aza has therapeutic potential for possible use of GSTs in targeted enzyme-prodrug treatment of diseases. Based on the assumed catalytic mechanism and computational docking of Aza to the active site of the enzyme, active-site residues were selected for construction of focused mutant libraries, which were thereafter screened for Aza activity. Mutants with elevated Aza activity were identified, DNA sequenced, and the proteins purified. The two most active mutants showed up to 70-fold higher catalytic efficiency than the parental GST A2-2. The structure of the most active triple mutant (L107G/L108D/F222H) enzyme was determined by X-ray crystallography demonstrating significant changes in the topography of the active site facilitating productive binding of Aza as a substrate. PubMed: 22444596DOI: 10.1016/j.chembiol.2012.01.021 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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