3f0q: Difference between revisions
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==Staphylococcus aureus dihydrofolate reductase complexed with NADPH and 2,4-Diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine== | |||
<StructureSection load='3f0q' size='340' side='right' caption='[[3f0q]], [[Resolution|resolution]] 2.08Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3f0q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staab Staab]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3F0Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3F0Q FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52V:5-[(3S)-3-(5-METHOXY-2,6-DIMETHYLBIPHENYL-3-YL)BUT-1-YN-1-YL]-6-METHYLPYRIMIDINE-2,4-DIAMINE'>52V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3f0b|3f0b]], [[3f0s|3f0s]], [[3f0u|3f0u]], [[3f0v|3f0v]], [[3f0x|3f0x]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dfrB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=273036 STAAB])</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=3f0q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f0q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3f0q RCSB], [http://www.ebi.ac.uk/pdbsum/3f0q PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/Q2YY41_STAAB Q2YY41_STAAB]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis (By similarity).[PIRNR:PIRNR000194] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f0/3f0q_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K( *), to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance. | |||
Predicting resistance mutations using protein design algorithms.,Frey KM, Georgiev I, Donald BR, Anderson AC Proc Natl Acad Sci U S A. 2010 Jul 19. PMID:20643959<ref>PMID:20643959</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Dihydrofolate reductase|Dihydrofolate reductase]] | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Dihydrofolate reductase]] | [[Category: Dihydrofolate reductase]] | ||
[[Category: Staab]] | [[Category: Staab]] | ||
[[Category: Anderson, A C | [[Category: Anderson, A C]] | ||
[[Category: Frey, K M | [[Category: Frey, K M]] | ||
[[Category: Liu, J | [[Category: Liu, J]] | ||
[[Category: Lombardo, M N | [[Category: Lombardo, M N]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
Revision as of 01:54, 25 December 2014
Staphylococcus aureus dihydrofolate reductase complexed with NADPH and 2,4-Diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidineStaphylococcus aureus dihydrofolate reductase complexed with NADPH and 2,4-Diamino-5-[3-(3-methoxy-5-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
Structural highlights
Function[Q2YY41_STAAB] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis (By similarity).[PIRNR:PIRNR000194] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedDrug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K( *), to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance. Predicting resistance mutations using protein design algorithms.,Frey KM, Georgiev I, Donald BR, Anderson AC Proc Natl Acad Sci U S A. 2010 Jul 19. PMID:20643959[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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