5foc: Difference between revisions
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<StructureSection load='5foc' size='340' side='right'caption='[[5foc]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='5foc' size='340' side='right'caption='[[5foc]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5foc]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5foc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FOC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FOC FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</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=5foc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5foc OCA], [https://pdbe.org/5foc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5foc RCSB], [https://www.ebi.ac.uk/pdbsum/5foc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5foc ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/C6KT64_PLAF7 C6KT64_PLAF7] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Plasmodium falciparum 3D7]] | ||
[[Category: Ahyong V]] | |||
[[Category: Ahyong | [[Category: Alley MRK]] | ||
[[Category: Alley | [[Category: Cooper R]] | ||
[[Category: Cooper | [[Category: Cusack S]] | ||
[[Category: Cusack | [[Category: DeRisi J]] | ||
[[Category: DeRisi | [[Category: Dong C]] | ||
[[Category: Dong | [[Category: Freund YR]] | ||
[[Category: Freund | [[Category: Guo D]] | ||
[[Category: Guo | [[Category: Gut J]] | ||
[[Category: Gut | [[Category: Hernandez VS]] | ||
[[Category: Hernandez | [[Category: Legac J]] | ||
[[Category: Legac | [[Category: Li X]] | ||
[[Category: Li | [[Category: Palencia A]] | ||
[[Category: Palencia | [[Category: Rosenthal PJ]] | ||
[[Category: Rosenthal | [[Category: Sonoiki E]] | ||
[[Category: Sonoiki | |||
Revision as of 10:01, 19 July 2023
Crystal structure of the P.falciparum cytosolic leucyl-tRNA synthetase editing domain (space group P21)Crystal structure of the P.falciparum cytosolic leucyl-tRNA synthetase editing domain (space group P21)
Structural highlights
FunctionPublication Abstract from PubMedThere 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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