4tu5: Difference between revisions
No edit summary |
No edit summary |
||
| (4 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1062)== | ==Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1062)== | ||
<StructureSection load='4tu5' size='340' side='right' caption='[[4tu5]], [[Resolution|resolution]] 2.16Å' scene=''> | <StructureSection load='4tu5' size='340' side='right'caption='[[4tu5]], [[Resolution|resolution]] 2.16Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4tu5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TU5 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4tu5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_RF122 Staphylococcus aureus RF122]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TU5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TU5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=06W:6-ETHYL-5-{(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL}PYRIMIDINE-2,4-DIAMINE'>06W</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.161Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=06W:6-ETHYL-5-{(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL}PYRIMIDINE-2,4-DIAMINE'>06W</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></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=4tu5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tu5 OCA], [https://pdbe.org/4tu5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tu5 RCSB], [https://www.ebi.ac.uk/pdbsum/4tu5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tu5 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/A0A0M3KKX1_STAAB A0A0M3KKX1_STAAB] 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 18: | Line 18: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4tu5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Staphylococcus aureus RF122]] | ||
[[Category: Anderson AC]] | |||
[[Category: Reeve SM]] | |||
[[Category: | |||
[[Category: | |||
Latest revision as of 10:23, 27 September 2023
Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1062)Staphylococcus aureus Dihydrofolate Reductase complexed with NADPH and 6-ETHYL-5-[(3S)-3-[3-METHOXY-5-(PYRIDIN-4-YL)PHENYL]BUT-1-YN-1-YL]PYRIMIDINE-2,4-DIAMINE (UCP1062)
Structural highlights
FunctionA0A0M3KKX1_STAAB 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 PubMedWhile antifolates such as Bactrim (trimethoprim-sulfamethoxazole; TMP-SMX) continue to play an important role in treating community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), resistance-conferring mutations, specifically F98Y of dihydrofolate reductase (DHFR), have arisen and compromise continued use. In an attempt to extend the lifetime of this important class, we have developed a class of propargyl-linked antifolates (PLAs) that exhibit potent inhibition of the enzyme and bacterial strains. Probing the role of the configuration at the single propargylic stereocenter in these inhibitors required us to develop a new approach to nonracemic 3-aryl-1-butyne building blocks by the pairwise use of asymmetric conjugate addition and aldehyde dehydration protocols. Using this new route, a series of nonracemic PLA inhibitors was prepared and shown to possess potent enzyme inhibition (IC50 values <50 nM), antibacterial effects (several with MIC values <1 mug/mL) and to form stable ternary complexes with both wild-type and resistant mutants. Unexpectedly, crystal structures of a pair of individual enantiomers in the wild-type DHFR revealed that the single change in configuration of the stereocenter drove the selection of an alternative NADPH cofactor, with the minor alpha-anomer appearing with R-27. Remarkably, this cofactor switching becomes much more prevalent when the F98Y mutation is present. The observation of cofactor site plasticity leads to a postulate for the structural basis of TMP resistance in DHFR and also suggests design strategies that can be used to target these resistant enzymes. Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus.,Keshipeddy S, Reeve SM, Anderson AC, Wright DL J Am Chem Soc. 2015 Jul 8. PMID:26098608[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||