Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates.
Acta Crystallogr D Struct Biol
; 75(Pt 7): 682-693, 2019 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-31282477
Tuberculosis is a disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single infectious pathogen, with a high prevalence in developing countries in Africa and Asia. There still is a need for the development or repurposing of novel therapies to combat this disease owing to the long-term nature of current therapies and because of the number of reported resistant strains. Here, structures of dihydrofolate reductase from M. tuberculosis (MtDHFR), which is a key target of the folate pathway, are reported in complex with four antifolates, pyrimethamine, cycloguanil, diaverdine and pemetrexed, and its substrate dihydrofolate in order to understand their binding modes. The structures of all of these complexes were obtained in the closed-conformation state of the enzyme and a fine structural analysis indicated motion in key regions of the substrate-binding site and different binding modes of the ligands. In addition, the affinities, through Kd measurement, of diaverdine and methotrexate have been determined; MtDHFR has a lower affinity (highest Kd) for diaverdine than pyrimethamine and trimethoprim, and a very high affinity for methotrexate, as expected. The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidrofolato Desidrogenase
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Ácido Fólico
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Antagonistas do Ácido Fólico
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Mycobacterium tuberculosis
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Acta Crystallogr D Struct Biol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos