2c2s
From Proteopedia
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| - | [[Image:2c2s.gif|left|200px]]<br /><applet load="2c2s" size=" | + | [[Image:2c2s.gif|left|200px]]<br /><applet load="2c2s" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2c2s, resolution 1.40Å" /> | caption="2c2s, resolution 1.40Å" /> | ||
'''HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE'''<br /> | '''HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE'''<br /> | ||
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==Overview== | ==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. | 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. | ||
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| - | ==Disease== | ||
| - | Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=126060 126060]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2C2S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NDP, 34B and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Known structural/functional Site: <scene name='pdbsite=AC1:Gol Binding Site For Chain B'>AC1</scene>. Full crystallographic information is available from [http:// | + | 2C2S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NDP:'>NDP</scene>, <scene name='pdbligand=34B:'>34B</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] Known structural/functional Site: <scene name='pdbsite=AC1:Gol Binding Site For Chain B'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C2S OCA]. |
==Reference== | ==Reference== | ||
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[[Category: reductase]] | [[Category: reductase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:28:03 2008'' |
Revision as of 12:28, 23 January 2008
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HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE
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.
About this Structure
2C2S is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Known structural/functional Site: . 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
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