4km2

Crystal structure of Dihydrofolate reductase from Mycobacterium tuberculosis in an open conformation in complex with trimethoprimCrystal structure of Dihydrofolate reductase from Mycobacterium tuberculosis in an open conformation in complex with trimethoprim

Structural highlights 4km2 is a 2 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , Related: 4kl9, 4klx, 4km0, 4kne Gene: dfrA, folA, MT2833, MTV002.28c, Rv2763c ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Dihydrofolate reductase, with EC number 1.5.1.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMed 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. Mycobacterium tuberculosis Dihydrofolate Reductase Reveals Two Conformational States and a Possible Low Affinity Mechanism to Antifolate Drugs.,Dias MV, Tyrakis P, Domingues RR, Leme AF, Blundell TL Structure. 2013 Nov 6. pii: S0969-2126(13)00395-X. doi:, 10.1016/j.str.2013.09.022. PMID:24210757 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 4km2, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image