Advanced search
Start date
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates

Full text
Ribeiro, Joao Augusto [1, 2] ; Chavez-Pacheco, Sair Maximo [2] ; de Oliveira, Gabriel Stephani [2] ; Silva, Catharina dos Santos [2] ; Pimenta Giudice, Joao Henrique [2] ; Libreros-Zuniga, Gerardo Andres [2, 3, 4] ; Bertacine Dias, Marcio Vinicius [1, 5, 2, 3]
Total Authors: 7
[1] Univ Estadual Campinas, Inst Biol, Campinas, SP - Brazil
[2] Univ Sao Paulo, Dept Microbiol, Inst Biomed Sci, Ave Prof Lineu Prestes 1374, BR-05508000 Sao Paulo - Brazil
[3] Univ Sao Paulo State, IBILCE, Rua Cristevao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil
[4] Univ Valle, Dept Microbiol, Calle 4B 36-00, Cali - Colombia
[5] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands - England
Total Affiliations: 5
Document type: Journal article
Web of Science Citations: 0

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 K-d measurement, of diaverdine and methotrexate have been determined; MtDHFR has a lower affinity (highest K-d) 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. (AU)

FAPESP's process: 13/15906-5 - Fragment based drug discovery (FBDD) applied to two enzymes of folate biosynthetic pathway from Mycobacterium tuberculosis
Grantee:João Augusto Ribeiro
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 15/09188-8 - Biosynthesis of polyether and aminoglycoside antibiotics: structural investigation of unusual enzymes or with synthetic biology applicability
Grantee:Marcio Vinicius Bertacine Dias
Support type: Regular Research Grants
FAPESP's process: 18/00351-1 - Applied structural biology involved in the biosynthesis of natural products: biotechnolgical aplications and study of unusual molecular reactions
Grantee:Marcio Vinicius Bertacine Dias
Support type: Regular Research Grants
FAPESP's process: 14/24486-2 - Structural basis of sensibility of Mycobacterium tuberculosis and M. leprae dihydropteroate synthase to the sulfonamide drugs
Grantee:João Henrique Pimenta Giudice
Support type: Scholarships in Brazil - Master
FAPESP's process: 16/18721-4 - Structural basis of the elongation and cell division control in Mycobacterium tuberculosis and identification of new drug hits based in fragment trials
Grantee:Catharina dos Santos Silva
Support type: Scholarships in Brazil - Doctorate (Direct)