5ZH2

CRYSTAL STRUCTURE OF PfKRS WITH INHIBITOR CLADO-5

5ZH2 の概要

• エントリーDOI: 10.2210/pdb5zh2/pdb
• 分子名称: Lysine-tRNA ligase, LYSINE, (3R)-6,8-dihydroxy-3-{[(2R,6R)-6-methyloxan-2-yl]methyl}-3,4-dihydro-1H-2-benzopyran-1-one, ... (5 entities in total)
• 機能のキーワード: krs, ligase-ligase inhibitor complex, ligase
• 由来する生物種: Plasmodium falciparum NF54 (Plasmodium falciparum (isolate NF54))
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 118643.99

構造登録者

Babbar, P.,Malhotra, N.,Sharma, M.,Harlos, K.,Reddy, D.S.,Manickam, Y.,Sharma, A. (登録日: 2018-03-11, 公開日: 2018-06-27, 最終更新日: 2023-11-22)

主引用文献

Das, P.,Babbar, P.,Malhotra, N.,Sharma, M.,Jachak, G.R.,Gonnade, R.G.,Shanmugam, D.,Harlos, K.,Yogavel, M.,Sharma, A.,Reddy, D.S.
Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite
J. Med. Chem., 61:5664-5678, 2018

PubMed Abstract: 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.

PubMed: 29779382
DOI: 10.1021/acs.jmedchem.8b00565

実験手法

X-RAY DIFFRACTION (2.66 Å)