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==CRYSTAL STRUCTURE OF PfKRS WITH INHIBITOR CLADO-5== | |||
<StructureSection load='5zh2' size='340' side='right'caption='[[5zh2]], [[Resolution|resolution]] 2.66Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5zh2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_NF54 Plasmodium falciparum NF54]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZH2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZH2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.66Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9CU:(3R)-6,8-dihydroxy-3-{[(2R,6R)-6-methyloxan-2-yl]methyl}-3,4-dihydro-1H-2-benzopyran-1-one'>9CU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=LYS:LYSINE'>LYS</scene>, <scene name='pdbligand=MPO:3[N-MORPHOLINO]PROPANE+SULFONIC+ACID'>MPO</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=5zh2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zh2 OCA], [https://pdbe.org/5zh2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zh2 RCSB], [https://www.ebi.ac.uk/pdbsum/5zh2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zh2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/W7JP72_PLAFO W7JP72_PLAFO] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development. | |||
Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.,Das P, Babbar P, Malhotra N, Sharma M, Jachak GR, Gonnade RG, Shanmugam D, Harlos K, Yogavel M, Sharma A, Reddy DS J Med Chem. 2018 Jun 4. doi: 10.1021/acs.jmedchem.8b00565. PMID:29779382<ref>PMID:29779382</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5zh2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Plasmodium falciparum NF54]] | |||
[[Category: Babbar P]] | |||
[[Category: Harlos K]] | |||
[[Category: Malhotra N]] | |||
[[Category: Manickam Y]] | |||
[[Category: Reddy DS]] | |||
[[Category: Sharma A]] | |||
[[Category: Sharma M]] | |||
Latest revision as of 11:54, 22 November 2023
CRYSTAL STRUCTURE OF PfKRS WITH INHIBITOR CLADO-5CRYSTAL STRUCTURE OF PfKRS WITH INHIBITOR CLADO-5
Structural highlights
FunctionPublication Abstract from PubMedThe dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development. Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.,Das P, Babbar P, Malhotra N, Sharma M, Jachak GR, Gonnade RG, Shanmugam D, Harlos K, Yogavel M, Sharma A, Reddy DS J Med Chem. 2018 Jun 4. doi: 10.1021/acs.jmedchem.8b00565. PMID:29779382[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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