4ky8
From Proteopedia
(Difference between revisions)
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| - | + | ==Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, methotrexate, FdUMP and 4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)-2-chlorophenyl)-L-glutamic acid== | |
| - | + | <StructureSection load='4ky8' size='340' side='right' caption='[[4ky8]], [[Resolution|resolution]] 3.08Å' scene=''> | |
| - | { | + | == Structural highlights == |
| - | + | <table><tr><td colspan='2'>[[4ky8]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Cryptosporidium_hominis Cryptosporidium hominis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KY8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KY8 FirstGlance]. <br> | |
| - | ==Function== | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1UF:N-{4-[(2-AMINO-6-METHYL-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)SULFANYL]-2-CHLOROBENZOYL}-L-GLUTAMIC+ACID'>1UF</scene>, <scene name='pdbligand=MTX:METHOTREXATE'>MTX</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=UFP:5-FLUORO-2-DEOXYURIDINE-5-MONOPHOSPHATE'>UFP</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qzf|1qzf]], [[3hj3|3hj3]], [[3dl5|3dl5]], [[3dl6|3dl6]], [[2oip|2oip]]</td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Chro.40506, TS-DHFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=237895 Cryptosporidium hominis])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ky8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ky8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ky8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ky8 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
[[http://www.uniprot.org/uniprot/Q5CGA3_CRYHO Q5CGA3_CRYHO]] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] | [[http://www.uniprot.org/uniprot/Q5CGA3_CRYHO Q5CGA3_CRYHO]] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Cryptosporidiosis, a gastrointestinal disease caused by a protozoan Cryptosporidium hominis is often fatal in immunocompromised individuals. There is little clinical data to show that the existing treatment by nitazoxanide and paromomycin is effective in immunocompromised individuals.1,2 Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are essential enzymes in the folate biosynthesis pathway and are well established as drug targets in cancer and malaria. A novel series of classical antifolates, 2-amino-4-oxo-5-substituted pyrrolo[2,3-d]pyrimidines have been evaluated as Cryptosporidium hominis thymidylate synthase (ChTS) inhibitors. Crystal structure in complex with the most potent compound, a 2'-chlorophenyl with a sulfur bridge with a Ki of 8.83+/-0.67nM is discussed in terms of several Van der Waals, hydrophobic and hydrogen bond interactions with the protein residues and the substrate analog 5-fluorodeoxyuridine monophosphate. Of these interactions, two interactions with the non-conserved residues (A287 and S290) offer an opportunity to develop ChTS specific inhibitors. Compound 6 serves as a lead compound for analog design and its crystal structure provides clues for the design of ChTS specific inhibitors. | ||
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| + | Substituted pyrrolo[2,3-d]pyrimidines as Cryptosporidium hominis thymidylate synthase inhibitors.,Kumar VP, Frey KM, Wang Y, Jain HK, Gangjee A, Anderson KS Bioorg Med Chem Lett. 2013 Jul 24. pii: S0960-894X(13)00882-2. doi:, 10.1016/j.bmcl.2013.07.037. PMID:23927969<ref>PMID:23927969</ref> | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | == | + | ==See Also== |
| - | + | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Cryptosporidium hominis]] | [[Category: Cryptosporidium hominis]] | ||
| - | [[Category: Anderson, K S | + | [[Category: Anderson, K S]] |
| - | [[Category: Kumar, V P | + | [[Category: Kumar, V P]] |
[[Category: Bifunctional enzyme]] | [[Category: Bifunctional enzyme]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Oxidoreductase-inhibitor complex]] | [[Category: Oxidoreductase-inhibitor complex]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
Revision as of 06:15, 25 December 2014
Crystal structure of TS-DHFR from Cryptosporidium hominis in complex with NADPH, methotrexate, FdUMP and 4-((2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)-2-chlorophenyl)-L-glutamic acid
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