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==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)==
<StructureSection load='4osg' size='340' side='right' caption='[[4osg]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='4osg' size='340' side='right'caption='[[4osg]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4osg]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OSG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OSG FirstGlance]. <br>
<table><tr><td colspan='2'>[[4osg]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_CG43 Klebsiella pneumoniae CG43]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OSG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OSG FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=06U:6-ETHYL-5-{(3R)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL}PYRIMIDINE-2,4-DIAMINE'>06U</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4or7|4or7]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=06U:6-ETHYL-5-{(3R)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL}PYRIMIDINE-2,4-DIAMINE'>06U</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EOH:ETHANOL'>EOH</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4osg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4osg OCA], [https://pdbe.org/4osg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4osg RCSB], [https://www.ebi.ac.uk/pdbsum/4osg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4osg ProSAT]</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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Resistance 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<ref>PMID:25288083</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dihydrofolate reductase]]
[[Category: Klebsiella pneumoniae CG43]]
[[Category: Anderson, A C]]
[[Category: Large Structures]]
[[Category: Lamb, K M]]
[[Category: Anderson AC]]
[[Category: Hydride shift]]
[[Category: Lamb KM]]
[[Category: Oxidoreductase]]
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

Latest revision as of 15:41, 1 March 2024

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

4osg is a 4 chain structure with sequence from Klebsiella pneumoniae CG43. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:, , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

4osg, resolution 2.70Å

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