|
|
| (One intermediate revision by the same user not shown) |
| Line 3: |
Line 3: |
| <StructureSection load='5fo4' size='340' side='right'caption='[[5fo4]], [[Resolution|resolution]] 1.85Å' scene=''> | | <StructureSection load='5fo4' size='340' side='right'caption='[[5fo4]], [[Resolution|resolution]] 1.85Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[5fo4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FO4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FO4 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[5fo4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FO4 FirstGlance]. <br> |
| </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5foc|5foc]], [[5fod|5fod]], [[5fof|5fof]], [[5fog|5fog]], [[5fol|5fol]], [[5fom|5fom]], [[5fon|5fon]]</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]] 1.85Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PFF1095W ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5833 PLAFA])</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=5fo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fo4 OCA], [https://pdbe.org/5fo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fo4 RCSB], [https://www.ebi.ac.uk/pdbsum/5fo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fo4 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/Leucine--tRNA_ligase Leucine--tRNA ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.1.1.4 6.1.1.4] </span></td></tr>
| |
| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fo4 OCA], [http://pdbe.org/5fo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fo4 RCSB], [http://www.ebi.ac.uk/pdbsum/5fo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fo4 ProSAT]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/C6KT64_PLAF7 C6KT64_PLAF7] |
| There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (IC50 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (ED90 7.4 and 16.2 mg/kg, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with step-wise increases in concentration of AN6426. Resistant clones were characterized by whole genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [14C]leucine incorporation by cultured wild type, but not resistant parasites. The growth of resistant, but not wild type parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity, and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.
| |
| | |
| Anti-malarial benzoxaboroles target P. falciparum leucyl-tRNA synthetase.,Sonoiki E, Palencia A, Guo D, Ahyong V, Dong C, Li X, Hernandez VS, Zhang YK, Choi W, Gut J, Legac J, Cooper R, Alley MR, Freund YR, DeRisi J, Cusack S, Rosenthal PJ Antimicrob Agents Chemother. 2016 Jun 6. pii: AAC.00820-16. PMID:27270277<ref>PMID:27270277</ref>
| |
| | |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| |
| </div>
| |
| <div class="pdbe-citations 5fo4" style="background-color:#fffaf0;"></div>
| |
| == References ==
| |
| <references/>
| |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Leucine--tRNA ligase]] | | [[Category: Plasmodium falciparum]] |
| [[Category: Plafa]]
| | [[Category: Ahyong V]] |
| [[Category: Ahyong, V]] | | [[Category: Alley MRK]] |
| [[Category: Alley, M R.K]] | | [[Category: Cooper R]] |
| [[Category: Cooper, R]] | | [[Category: Cusack S]] |
| [[Category: Cusack, S]] | | [[Category: DeRisi J]] |
| [[Category: DeRisi, J]] | | [[Category: Dong C]] |
| [[Category: Dong, C]] | | [[Category: Freund YR]] |
| [[Category: Freund, Y R]] | | [[Category: Guo D]] |
| [[Category: Guo, D]] | | [[Category: Gut J]] |
| [[Category: Gut, J]] | | [[Category: Hernandez VS]] |
| [[Category: Hernandez, V S]] | | [[Category: Legac J]] |
| [[Category: Legac, J]] | | [[Category: Li X]] |
| [[Category: Li, X]] | | [[Category: Palencia A]] |
| [[Category: Palencia, A]] | | [[Category: Rosenthal PJ]] |
| [[Category: Rosenthal, P J]] | | [[Category: Sonoiki E]] |
| [[Category: Sonoiki, E]] | |
| [[Category: Aminoacyl-trna synthetase]]
| |
| [[Category: Ligase]]
| |
| [[Category: Novel boron inhibitors of leur]]
| |
| [[Category: P falciparum]]
| |
| [[Category: Protein biosynthesis]]
| |