2c2s
From Proteopedia
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| , resolution 1.40Å | |||||||
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| Sites: | |||||||
| Ligands: | , and | ||||||
| Activity: | Dihydrofolate reductase, with EC number 1.5.1.3 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE
Contents |
Overview
Two boron-containing, ortho-icosahedral carborane lipophilic antifolates were synthesized, and the crystal structures of their ternary complexes with human dihydrofolate reductase (DHFR) and dihydronicotinamide adenine dinucleotide phosphate were determined. The compounds were screened for activity against DHFR from six sources (human, rat liver, Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and Lactobacillus casei) and showed good to modest activity against these enzymes. The compounds were also tested for antibacterial activity against L. casei, M. tuberculosis H37Ra, and three M. avium strains and for cytotoxic activity against seven different human tumor cell lines. Antibacterial and cytotoxic activity was modest, with one sample, the closo-carborane 4, showing about 10-fold greater activity. The less toxic nido-carborane 2 was also tested as a candidate for boron neutron capture therapy, but showed poor tumor retention and low selectivity ratios for boron distribution in tumor tissue versus normal tissue.
Disease
Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]
About this Structure
2C2S is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation., Reynolds RC, Campbell SR, Fairchild RG, Kisliuk RL, Micca PL, Queener SF, Riordan JM, Sedwick WD, Waud WR, Leung AK, Dixon RW, Suling WJ, Borhani DW, J Med Chem. 2007 Jul 12;50(14):3283-9. Epub 2007 Jun 15. PMID:17569517
Page seeded by OCA on Thu Mar 20 16:10:04 2008
