4osg: Difference between revisions
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<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=4osg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4osg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4osg RCSB], [http://www.ebi.ac.uk/pdbsum/4osg PDBsum]</span></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=4osg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4osg OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4osg RCSB], [http://www.ebi.ac.uk/pdbsum/4osg PDBsum]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/U5M636_KLEPN U5M636_KLEPN]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.[PIRNR:PIRNR000194] | |||
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== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Revision as of 13:14, 25 December 2014
Klebsiella pneumoniae complexed with NADPH and 6-ethyl-5-[(3R)-3-[3-methoxyl-5-(pyridine-4-yl)phenyl]but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP1006)Klebsiella pneumoniae complexed with NADPH and 6-ethyl-5-[(3R)-3-[3-methoxyl-5-(pyridine-4-yl)phenyl]but-1-yn-1-yl]pyrimidine-2,4-diamine (UCP1006)
Structural highlights
Function[U5M636_KLEPN] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.[PIRNR:PIRNR000194] Publication Abstract from PubMedResistance to the antibacterial antifolate trimethoprim (TMP) is increasing in members of the family Enterobacteriaceae, driving the design of next-generation antifolates effective against these Gram-negative pathogens. The propargyl-linked antifolates are potent inhibitors of dihydrofolate reductases (DHFR) from several TMP-sensitive and -resistant species, including Klebsiella pneumoniae. Recently, we have determined that these antifolates inhibit the growth of strains of K. pneumoniae, some with MIC values of 1 mug/ml. In order to further the design of potent and selective antifolates against members of the Enterobacteriaceae, we determined the first crystal structures of K. pneumoniae DHFR bound to two of the propargyl-linked antifolates. These structures highlight that interactions with Leu 28, Ile 50, Ile 94, and Leu 54 are necessary for potency; comparison with structures of human DHFR bound to the same inhibitors reveal differences in residues (N64E, P61G, F31L, and V115I) and loop conformations (residues 49 to 53) that may be exploited for selectivity. Crystal Structures of Klebsiella pneumoniae Dihydrofolate Reductase Bound to Propargyl-Linked Antifolates Reveal Features for Potency and Selectivity.,Lamb KM, Lombardo MN, Alverson J, Priestley ND, Wright DL, Anderson AC Antimicrob Agents Chemother. 2014 Dec;58(12):7484-91. doi: 10.1128/AAC.03555-14. , Epub 2014 Oct 6. PMID:25288083[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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