4KM0

Crystal structure of dihydrofolate reductase from Mycobacterium tuberculosis in complex with pyrimethamine

Summary for 4KM0

• Entry DOI: 10.2210/pdb4km0/pdb
• Related: 4KL9 4KLX 4KM2 4KNE
• Descriptor: Dihydrofolate reductase, 5-(4-CHLORO-PHENYL)-6-ETHYL-PYRIMIDINE-2,4-DIAMINE, 2'-MONOPHOSPHOADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: reductase, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 41176.51

Authors

Dias, M.V.B.,Tyrakis, P.,Blundell, T.L. (deposition date: 2013-05-07, release date: 2013-12-25, Last modification date: 2024-02-28)

Primary citation

Dias, M.V.,Tyrakis, P.,Domingues, R.R.,Paes Leme, A.F.,Blundell, T.L.
Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.
Structure, 22:94-103, 2014

PubMed Abstract: Inhibition of the biosynthesis of tetrahydrofolate (THF) has long been a focus in the treatment of both cancer and infectious diseases. Dihydrofolate reductase (DHFR), which catalyzes the last step, is one of the most thoroughly explored targets of this pathway, but there are no DHFR inhibitors used for tuberculosis treatment. Here, we report a structural, site-directed mutagenesis and calorimetric analysis of Mycobacterium tuberculosis DHFR (MtDHFR) in complex with classical DHFR inhibitors. Our study provides insights into the weak inhibition of MtDHFR by trimethoprim and other antifolate drugs, such as pyrimethamine and cycloguanil. The construction of the mutant Y100F, together with calorimetric studies, gives insights into low affinity of MtDHFR for classical DHFR inhibitors. Finally, the structures of MtDHFR in complex with pyrimethamine and cycloguanil define important interactions in the active site and provide clues to the more effective design of antibiotics targeted against MtDHFR.

PubMed: 24210757
DOI: 10.1016/j.str.2013.09.022

Experimental method

X-RAY DIFFRACTION (1.3 Å)