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| | <StructureSection load='4q6a' size='340' side='right'caption='[[4q6a]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='4q6a' size='340' side='right'caption='[[4q6a]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4q6a]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus_muf168 Staphylococcus aureus muf168]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q6A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4q6a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_MUF168 Staphylococcus aureus MUF168]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Q6A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 2.099Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4q67|4q67]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrB, Y000_11620 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1435480 Staphylococcus aureus MUF168])</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=4q6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q6a OCA], [https://pdbe.org/4q6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4q6a RCSB], [https://www.ebi.ac.uk/pdbsum/4q6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4q6a ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4q6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q6a OCA], [http://pdbe.org/4q6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4q6a RCSB], [http://www.ebi.ac.uk/pdbsum/4q6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4q6a ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Function == | |
| - | [[http://www.uniprot.org/uniprot/W7NDF6_STAAU W7NDF6_STAAU]] 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 == |
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| | ==See Also== | | ==See Also== |
| - | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydrofolate reductase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Staphylococcus aureus muf168]] | + | [[Category: Staphylococcus aureus MUF168]] |
| - | [[Category: Anderson, A C]] | + | [[Category: Anderson AC]] |
| - | [[Category: Reeve, S M]] | + | [[Category: Reeve SM]] |
| - | [[Category: Oxidoreductase]]
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| Structural highlights
Publication Abstract from PubMed
Methods to accurately predict potential drug target mutations in response to early-stage leads could drive the design of more resilient first generation drug candidates. In this study, a structure-based protein design algorithm (K* in the OSPREY suite) was used to prospectively identify single-nucleotide polymorphisms that confer resistance to an experimental inhibitor effective against dihydrofolate reductase (DHFR) from Staphylococcus aureus. Four of the top-ranked mutations in DHFR were found to be catalytically competent and resistant to the inhibitor. Selection of resistant bacteria in vitro reveals that two of the predicted mutations arise in the background of a compensatory mutation. Using enzyme kinetics, microbiology, and crystal structures of the complexes, we determined the fitness of the mutant enzymes and strains, the structural basis of resistance, and the compensatory relationship of the mutations. To our knowledge, this work illustrates the first application of protein design algorithms to prospectively predict viable resistance mutations that arise in bacteria under antibiotic pressure.
Protein design algorithms predict viable resistance to an experimental antifolate.,Reeve SM, Gainza P, Frey KM, Georgiev I, Donald BR, Anderson AC Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):749-54. doi:, 10.1073/pnas.1411548112. Epub 2014 Dec 31. PMID:25552560[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Reeve SM, Gainza P, Frey KM, Georgiev I, Donald BR, Anderson AC. Protein design algorithms predict viable resistance to an experimental antifolate. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):749-54. doi:, 10.1073/pnas.1411548112. Epub 2014 Dec 31. PMID:25552560 doi:http://dx.doi.org/10.1073/pnas.1411548112
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