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6CQA

E. coli DHFR complex with inhibitor AMPQD

Summary for 6CQA
Entry DOI10.2210/pdb6cqa/pdb
DescriptorDihydrofolate reductase, SULFATE ION, 7-[(3-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine, ... (4 entities in total)
Functional Keywordsdhfr, dihydrofolate reductase, inhibitor, complex, oxidoreductase
Biological sourceEscherichia coli
Total number of polymer chains1
Total formula weight19344.70
Authors
Cao, H.,Rodrigues, J.,Benach, J.,Wasserman, S.,Morisco, L.,Koss, J.,Shakhnovich, E.,Skolnick, J. (deposition date: 2018-03-14, release date: 2019-01-09, Last modification date: 2023-10-04)
Primary citationCao, 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: 30564747
DOI: 10.1038/s42003-018-0236-y
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.2 Å)
Structure validation

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