6CW7
E. coli DHFR product complex with (6S)-5,6,7,8-TETRAHYDROFOLATE
Summary for 6CW7
| Entry DOI | 10.2210/pdb6cw7/pdb |
| Related | 6CQA 6CXK |
| Descriptor | Dihydrofolate reductase, (6S)-5,6,7,8-TETRAHYDROFOLATE, CHLORIDE ION, ... (5 entities in total) |
| Functional Keywords | dhfr, dihydrofolate reductase, tetrahydrofolate, complex, oxidoreductase |
| Biological source | Escherichia coli O6:H1 (strain CFT073 / ATCC 700928 / UPEC) |
| Total number of polymer chains | 1 |
| Total formula weight | 19497.23 |
| Authors | Cao, H.,Rodrigues, J.,Benach, J.,Frommelt, A.,Morisco, L.,Koss, J.,Shakhnovich, E.,Skolnick, J. (deposition date: 2018-03-30, release date: 2019-01-09, Last modification date: 2023-10-04) |
| Primary citation | Cao, H.,Gao, M.,Zhou, H.,Skolnick, J. The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release. Commun Biol, 1:226-226, 2018 Cited by PubMed Abstract: Dihydrofolate reductase (DHFR) catalyzes the stereospecific reduction of 7,8-dihydrofolate (FH2) to (6s)-5,6,7,8-tetrahydrofolate (FH4) via hydride transfer from NADPH. The consensus DHFR mechanism involves conformational changes between closed and occluded states occurring during the rate-limiting product release step. Although the Protein Data Bank (PDB) contains over 250 DHFR structures, the FH4 complex structure responsible for rate-limiting product release is unknown. We report to our knowledge the first crystal structure of an . DHFR:FH4 complex at 1.03 Å resolution showing distinct stabilizing interactions absent in FH2 or related (6R)-5,10-dideaza-FH4 complexes. We discover the time course of decay of the co-purified endogenous FH4 during crystal growth, with conversion from FH4 to FH2 occurring in 2-3 days. We also determine another occluded complex structure of DHFR with a slow-onset nanomolar inhibitor that contrasts with the methotrexate complex, suggesting a plausible strategy for designing DHFR antibiotics by targeting FH4 product conformations. PubMed: 30564747DOI: 10.1038/s42003-018-0236-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.03 Å) |
Structure validation
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