An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase–ligand complexes following further refinement. Issue 3 (7th March 2019)

• Record Type: Journal Article
• Authors: Bueno, Renata; Dawson, Alice; Hunter, William N.
• Is Part Of: Acta crystallographica. Volume 75:Issue 3(2019:Mar.)
• Page Start: 148
• Page End: 152
• Publication Date: 2019-03-07
• Subjects: methylenetetrahydrofolate dehydrogenase -- methenyltetrahydrofolate cyclohydrolase -- antifolates -- structure‐based ligand design -- structure validation -- re‐refinement; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X18018083
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : Further refinement of three methylenetetrahydrofolate dehydrogenase/cyclohydrolase–antifolate inhibitor complexes in the Protein Data Bank has produced models that allow a critical reassessment of ligand placement. One complex has a well ordered ligand in a catalytic site and the model provides an improved description of enzyme–inhibitor interactions. One ligand may adopt two conformations in the binding site rather than the single conformation described previously. There is no evidence to support the incorporation of the third compound in the model. Interpretation of the data supports a correlation between the models and the inhibition activity for two of the compounds. In the case of the third, inconsistencies were noted that would need to be addressed by further work. Abstract : The enzymes involved in folate metabolism are key drug targets for cell‐growth modulation, and accurate crystallographic structures provide templates to be exploited for structure‐based ligand design. In this context, three ternary complex structures of human methylenetetrahydrofolate dehydrogenase/cyclohydrolase have been published [Schmidt et al. (2000), Biochemistry, 39, 6325–6335] and potentially represent starting points for the development of new antifolate inhibitors. However, an inspection of the models and the deposited data revealed deficiencies and raised questions about the validity of the structures. A number of inconsistencies relating to the publication were also identified. Additional refinement was carried out with the deposited data, seeking to improve the models and to then validate the complex structures or correct the record. In one case, the inclusion of the inhibitor in the structure was supported and alterations to the model allowed details of enzyme–ligand interactions to be described that had not previously been discussed. For one weak inhibitor, the data suggested that the ligand may adopt two poses in the binding site, both with few interactions with the enzyme. In the third case, that of a potent inhibitor, inconsistencies were noted in the assignment of the chemical structure and there was no evidence to support the inclusion of the ligand in the active site.